Alternative titles; symbols
HGNC Approved Gene Symbol: TGFB1
SNOMEDCT: 34643004; ICD10CM: Q78.3;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:41,330,323-41,353,922 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | {Cystic fibrosis lung disease, modifier of} | 219700 | Autosomal recessive | 3 |
| Camurati-Engelmann disease | 131300 | Autosomal dominant | 3 | |
| Inflammatory bowel disease, immunodeficiency, and encephalopathy | 618213 | Autosomal recessive | 3 |
TGFB is a multifunctional peptide that controls proliferation, differentiation, and other functions in many cell types. TGFB acts synergistically with TGFA (190170) in inducing transformation. It also acts as a negative autocrine growth factor. Dysregulation of TGFB activation and signaling may result in apoptosis. Many cells synthesize TGFB and almost all of them have specific receptors for this peptide. TGFB1, TGFB2 (190220), and TGFB3 (190230) all function through the same receptor signaling systems (summary by Sporn et al., 1986 and Derynck et al., 2001).
Using oligonucleotide probes designed from a partial amino acid sequence of TGFB1 purified from blood platelets, Derynck et al. (1985) cloned TGFB1 from a genomic library derived from human term placenta mRNA. The deduced precursor protein contains 391 amino acids, of which the C-terminal 112 amino acids constitute the mature protein. An arg-arg dipeptide precedes the proteolytic cleavage site. The TGFB1 precursor contains 3 potential N-glycosylation sites. Northern blot analysis detected a 2.5-kb transcript in all solid tumors of meso-, endo- and ectoblastic origin tested and in tumors cell lines of hematopoietic origin. The transcript was also detected in normal peripheral blood lymphocytes and placenta; it was not detected in liver, although it was expressed by a hepatoma cell line. Nonreduced purified TGFB from human blood platelets showed an apparent molecular mass of about 25 kD. Under reducing conditions, it migrated with an apparent molecular mass of 12.5 kD, indicating that TGFB consists of 2 polypeptide chains linked by intermolecular disulfide bridges.
Derynck et al. (1987) determined that the TGFB1 precursor gene contains 7 exons and very large introns.
By somatic cell hybridization and in situ hybridization, Fujii et al. (1985, 1986) assigned TGFB to 19q13.1-q13.3 in man and to chromosome 7 in the mouse. Dickinson et al. (1990) mapped the Tgfb1 gene to mouse chromosome 7.
Dickinson et al. (1990) pointed out that high levels of TGFB1 mRNA and/or protein have been localized in developing cartilage, endochondral and membrane bone, and skin, suggesting a role in the growth and differentiation of these tissues.
Dubois et al. (1995) demonstrated in vitro that pro-TGFB1 was cleaved by furin (136950) to produce a biologically active TGFB1 protein. Expression of pro-TGFB1 in furin-deficient cells produced no TGFB1, whereas coexpression of pro-TGFB1 and furin led to processing of the precursor.
Blanchette et al. (1997) showed that furin mRNA levels were increased in rat synovial cells by the addition of TGFB1. This effect was eliminated by pretreatment with actinomycin-D, suggesting to them that regulation was at the gene transcription level. Treatment of rat synoviocytes and kidney fibroblasts with TGFB1 or TGFB2 (190220) resulted in increased pro-TGFB1 processing, as evidenced by the appearance of a 40-kD immunoreactive band corresponding to the TGFB1 amino-terminal pro-region. Treatment of these cells with TGFB2 resulted in a significant increase in extracellular mature TGFB1. Blanchette et al. (1997) concluded that TGFB1 upregulates gene expression of its own converting enzyme.
Heldin et al. (1997) discussed mechanisms used by members of the TGF-beta family to elicit their effects on target cells; see SMAD1 (601595).
SMAD proteins mediate TGFB signaling to regulate cell growth and differentiation. Stroschein et al. (1999) proposed a model of regulation of TGFB signaling by SnoN (165340) in which SnoN maintains the repressed state of TGFB target genes in the absence of ligand and participates in the negative feedback regulation of TGFB signaling. To initiate a negative feedback mechanism that permits a precise and timely regulation of TGFB signaling, TGFB also induces an increased expression of SnoN at a later stage, which in turn binds to SMAD heteromeric complexes and shuts off TGFB signaling.
Jang et al. (2001) determined that the human DAP-kinase (600831) promoter is activated by TGFB through the action of SMAD2 (601366), SMAD3 (603109), and SMAD4 (600993). Overexpression of DAP-kinase triggers apoptosis in the absence of TGFB, whereas inhibition of DAP-kinase activity protects cells from TGFB-induced apoptosis, blocks TGFB-induced release of cytochrome c from mitochondria, and prevents TGFB-induced dissipation of the mitochondrial membrane potential. Jang et al. (2001) concluded that DAP-kinase mediates TGFB-dependent apoptosis by linking SMADs to mitochondrial-based pro-apoptotic events.
Valderrama-Carvajal et al. (2002) studied the signaling pathway activated by inhibin and TGFB1 during apoptosis in mouse and human hematopoietic cell lines. They determined that the downstream effectors include SMAD (see 601595) and SHIP (601582), a 5-prime inositol phosphatase. Activation of the SMAD pathway induced SHIP expression, resulting in intracellular changes in phospholipid pools and inhibited phosphorylation of protein kinase B (AKT1; 164730).
Lin et al. (2004) demonstrated that cytoplasmic PML (102578) is an essential modulator of TGF-beta signaling. Primary cells from Pml-null mice are resistant to TGF-beta-dependent growth arrest, induction of cellular senescence, and apoptosis. These cells also have impaired phosphorylation and nuclear translocation of the TGF-beta signaling proteins Smad2 and Smad3, as well as impaired induction of TGF-beta target genes. Expression of cytoplasmic Pml is induced by TGF-beta. Furthermore, cytoplasmic Pml physically interacts with Smad2, Smad3, and SMAD anchor for receptor activation (SARA; 603755), and is required for association of Smad2 and Smad3 with Sara and for the accumulation of Sara and TGF-beta receptor in the early endosome. The PML-RAR-alpha (180240) oncoprotein of acute promyelocytic leukemia can antagonize cytoplasmic PML function, and acute promyelocytic leukemia cells have defects in TGF-beta signaling similar to those observed in Pml-null cells. Lin et al. (2004) concluded that their findings identified cytoplasmic PML as a critical TGF-beta receptor and further implicated deregulated TGF-beta signaling in cancer pathogenesis.
Using primary human hematopoietic cells and microarray analysis, Scandura et al. (2004) identified p57(KIP2) (600856) as the only cyclin-dependent kinase inhibitor induced by TGF-beta. Upregulation of p57 mRNA and protein occurred before TGF-beta-induced G1 cell cycle arrest, required transcription, and was mediated via a highly conserved region of the proximal p57 promoter. Upregulation of p57 was essential for TGF-beta-induced cell cycle arrest in these cells, since 2 different small interfering RNAs that prevented p57 upregulation blocked the cytostatic effects of TGF-beta on the hematopoietic cells.
Jobling et al. (2004) found that Tbgf1, Tgfb2, and Tgfb3 were expressed in scleral tissue and scleral fibroblasts of tree shrew pups. All 3 isoforms increased collagen production in scleral fibroblasts in a dose-dependent manner, and changes in Tgfb expression were observed during development of experimental myopia in these animals.
Shehata et al. (2004) found increased levels of TGFB1 in bone marrow, serum, and plasma of 13 patients with hairy cell leukemia compared to controls and patients with B-cell leukemia. In vitro studies showed that the hairy cells were the main source of TGFB1 mRNA. TGFB1 levels correlated with bone marrow fibrosis and infiltration of hairy cells. Bone marrow plasma from patients increased the synthesis of type I (see 120150) and type III (see 120180) procollagens at the mRNA and protein levels, and this fibrogenic activity was abolished by anti-TGFB1 antibodies. Shehata et al. (2004) concluded that TGFB1 is directly involved in the pathogenesis of bone marrow reticulin fibrosis in hairy cell leukemia.
Using real-time RT-PCR, immunofluorescence microscopy, flow cytometry, and immunohistochemistry, Liu et al. (2006) found that cultured mouse neurons expressed Tgfb and B7 (CD80; 112203). Neuron-T cell interaction led to upregulation of Tgfb, B7, B7.2 (CD86; 601020), and Tgfbr2 (190182) expression in neurons, which could be inhibited by blockade of Tnf (191160) and Ifng (147570) in T cells. Furthermore, neuron-T cell interaction increased expression of Zap70 (176947), Il2 (147680), and Il9 (146931) in T cells. T-cell proliferation was dependent on neuronal Tgfb and B7. Stimulation of encephalitogenic T-cell lines with neurons induced Tgfb, Tgfbr2, and Smad3 expression and resulted in conversion of the cells to a regulatory T-cell (Treg) phenotype expressing Tgfb, Ctla4 (123890), and Foxp3 (300292). These Treg cells were capable of suppressing encephalitogenic T cells and inhibited experimental autoimmune encephalomyelitis in vivo. Blocking the B7 and Tgfb pathways prevented central nervous system (CNS)-specific generation of Treg cells. Liu et al. (2006) concluded that neurons induce generation of Treg cells in the CNS that are instrumental in regulating CNS inflammation.
Cordenonsi et al. (2007) found that RTK/Ras/MAPK activity induces p53 (191170) N-terminal phosphorylation, enabling the interaction of p53 with the TGF-beta-activated SMADs. This mechanism confined mesoderm specification in Xenopus embryos and promoted TGF-beta cytostasis in human cells. Cordenonsi et al. (2007) concluded that these data indicated a mechanism to allow extracellular cues to specify the TGF-beta gene expression program.
TGF-beta converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of IL6 (147620), TGF-beta also promotes the differentiation of naive T lymphocytes into proinflammatory IL17 (603149) cytokine-producing T helper-17 (Th17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. Mucida et al. (2007) identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL6-driven induction of proinflammatory Th17 cells and promoting antiinflammatory regulatory T cell (Treg) differentiation. Mucida et al. (2007) concluded that a common metabolite can regulate the balance between pro- and antiinflammatory immunity.
Prante et al. (2007) found that exogenic TGFB1 significantly increased XT1 (608124) expression in human cardiac fibroblasts in a dose-dependent manner. Increased XT1 expression correlated with elevated chondroitin sulfate-glycosaminoglycan content.
Yang et al. (2008) confirmed that whereas IL1-beta (147720) and IL6 induce IL17A secretion from human central memory CD4+ T cells, TGF-beta and IL21 (605384) uniquely promote the differentiation of human naive CD4+ T cells into Th17 cells accompanied by expression of the transcription factor RORC2 (see 602943).
Veldhoen et al. (2008) found that Tgfb could reprogram Th2 cells to lose their characteristic profile and switch to IL9 secretion. In combination with Il4 (147780), Tgfb could directly drive the generation of Il9-producing T cells, or Th9 cells. Veldhoen et al. (2008) concluded that TGFB is a cytokine that influences, or fine tunes, fate decisions of T cells depending on the presence of other cytokines.
Using flow cytometric analysis, Casetti et al. (2009) demonstrated that, like alpha-beta T cells, gamma-delta cells can also function as Tregs that express FOXP3 when stimulated with phosphoantigen in the presence of TGFB1 and IL15 (600554).
Wandzioch and Zaret (2009) investigated how bone morphogenetic protein (BMP4; 112262), TGF-beta, and fibroblast growth factor signaling pathways converge on the earliest genes that elicit pancreas and liver induction in mouse embryos. These genes include ALB1 (103600), PROX1 (601546), HNF6 (604164), HNF1B (189907), and PDX1 (600733). The inductive network was found to be dynamic; it changed within hours. Different signals functioned in parallel to induce different early genes, and 2 permutations of signals induced liver progenitor domains, which revealed flexibility in cell programming. Also, the specification of pancreas and liver progenitors was restricted by the TGF-beta pathway.
Ghoreschi et al. (2010) showed that Th17 differentiation can occur in the absence of TGF-beta signaling. Neither IL6 nor IL23 (see 605580) alone efficiently generated Th17 cells; however, these cytokines in combination with IL1-beta effectively induced IL17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the IL17A, IL17F (606496), and RORC promoters proceeded without TGF-beta-1, allowing the generation of cells that coexpressed ROR-gamma-t (encoded by RORC) and Tbet (TBX21; 604895). Tbet+ROR-gamma-t+Th17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred Th17 cells generated with IL23 without TGF-beta-1 were pathogenic in this disease model. Ghoreschi et al. (2010) concluded that their data indicated an alternative mode for Th17 differentiation and that, consistent with genetic data linking IL23R (607562) with autoimmunity, their findings reemphasized the importance of IL23 and therefore may have therapeutic implications.
Luo et al. (2010) showed that TGF-beta signaling is involved in reproductive aging and germline quality control in C. elegans. Data generated from oocyte array studies suggested that TGF-beta is also involved in reproductive aging in humans and mice.
Tili et al. (2010) described a complex regulatory network involving GAM (ZNF512B; 617886), cell cycle regulators, TGF-beta effectors, and microRNAs (miRNAs) of the MIR17-92 (see MIR17HG, 609415) cluster. GAM impaired MYC (190080)-dependent induction of individual miRNAs of the MIR17-92 cluster and limited activation of genes responsive to the TGF-beta canonical pathway. Both TGF-beta and miRNAs of the MIR17-92 cluster in turn negatively regulated GAM expression via a feedback autoregulatory loop.
Zhang et al. (2019) identified the TGFB signaling pathway as a key upstream regulator of the age-dependent loss of dermal fat and decrease in adipogenesis and cathelidicin production in response to infection in human and mouse skin. TGFB2 and to a lesser extent TGFB1 suppressed the capacity of dermal fibroblasts to differentiate into adipocytes by decreasing the expression of proadipogenic genes, and promoted the loss of antimicrobial activity by increasing the expression of profibrotic and proinflammatory genes. Inhibition of TGFB receptor restored adipogenic and antimicrobial function of dermal fibroblasts in adult mice as well as in cultured primary human dermal fibroblasts.
Hu et al. (2020) used thermogenic adipose tissue from mice as a model system to show that T cells, specifically gamma-delta T cells, have a crucial role in promoting sympathetic innervation, at least in part by driving the expression of TGF-beta-1 in parenchymal cells via IL17 receptor C (IL17RC; 610925). Ablation of IL17RC specifically in adipose tissue reduced expression of TGF-beta-1 in adipocytes, impaired local sympathetic innervation, and caused obesity and other metabolic phenotypes that were consistent with defective thermogenesis; innervation could be fully rescued by restoring TGF-beta-1 expression. Ablating gamma-delta T-cells and the IL17RC signaling pathway also impaired sympathetic innervation in other tissues such as salivary glands. Hu et al. (2020) concluded that their findings demonstrated coordination between T cells and parenchymal cells to regulate sympathetic innervation.
Role in Duchenne Muscular Dystrophy
Using quantitative PCR in 15 cases of Duchenne muscular dystrophy (DMD; 310200) and 13 cases of Becker muscular dystrophy (BMD; 300376), as well as 11 spinal muscular atrophy patients (SMA; 253300) and 16 controls, Bernasconi et al. (1995) found that TGFB1 expression as measured by mRNA was greater in DMD and BMD patients than in controls. Fibrosis was significantly more prominent in DMD than in BMD, SMA, or controls. The proportion of connective tissue biopsies increased progressively with age in DMD patients, while TGFB1 levels peaked at 2 and 6 years of age. Bernasconi et al. (1995) concluded that expression of TGFB1 in the early stages of DMD may be critical in initiating muscle fibrosis, and suggested that antifibrosis treatment might slow progression of the disease, increasing the utility of gene therapy.
Role in Kidney Disease
Although transforming growth factor-beta plays a central role in tissue repair, this cytokine is, as pointed out by Border and Noble (1995), a double-edged sword with both therapeutic and pathologic potential. TGF-beta has been implicated also in the pathogenesis of adult respiratory distress syndrome (Shenkar et al., 1994), and the kidney seems to be particularly sensitive to TGF-beta-induced fibrogenesis. TGF-beta has been implicated as a cause of fibrosis in most forms of experimental and human kidney disease (Border and Noble, 1994).
As reviewed by Reeves and Andreoli (2000), transforming growth factor-beta contributes to progressive diabetic nephropathy (603933). Renal failure is a common and serious complication of longstanding diabetes mellitus, both type I (IDDM; 222100) and type II (NIDDM; 125853). The prognosis of diabetic nephropathy is very poor. Structural abnormalities include hypertrophy of the kidney, an increase in the thickness of glomerular basement membranes, and accumulation of extracellular matrix components in the glomerulus, resulting in nodular and diffuse glomerulosclerosis. The extent of matrix accumulation in both the glomeruli and interstitium correlates strongly with the degree of renal insufficiency and proteinuria. TGF-beta appears to play a role in the development of renal hypertrophy and accumulation of extracellular matrix in diabetes. It is known to have powerful fibrogenic actions. In both humans and animal models, TGF-beta mRNA and protein levels are significantly increased in the glomeruli and tubulointerstitium in diabetes. Sharma et al. (1996) found that short-term administration of TGF-beta neutralizing antibodies to rats with chemically induced diabetes prevented glomerular enlargement and suppressed the expression of genes encoding extracellular matrix components.
Further strong indications of the role of TGF-beta were provided by Ziyadeh et al. (2000), who tested whether chronic administration of anti-TGF-beta antibody could prevent renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type II diabetes that develops overt nephropathy. They found that treatment with the antibody, but not with IgG, significantly decreased plasma TGF-beta-1 concentration without decreasing plasma glucose concentration. Furthermore, it prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNA of COL4A1 (120130) and fibronectin (135600) was substantially attenuated; on the other hand, urinary excretion of albumin was not significantly affected by the treatment. Chen et al. (2003) found that treatment with anti-TGFB antibody partly reversed glomerular basement membrane thickening and mesangial matrix accumulation in db/db mice.
As to the downstream targets of TGF-beta that mediate the pathophysiology of diabetic nephropathy, Waldegger et al. (1999) identified a serine/threonine kinase, serum/glucocorticoid-regulated kinase (SGK; 602958) that is transcriptionally upregulated by TGF-beta in both macrophage and liver cell experimental systems. Lang et al. (2000) demonstrated that excessive extracellular glucose concentrations enhance SGK transcription, which in turn stimulates renal tubular sodium ion transport.
Azar et al. (2000) compared the levels of TGF-beta in the serum of groups of patients with IDDM and NIDDM divided according to the duration of their disease. Twenty-six normoalbuminuric patients with IDDM and 25 normoalbuminuric patients with NIDDM were divided into 3 groups according to the onset of their diabetes and were compared with 27 and 15 age-matched normal subjects, respectively. The authors concluded that in normoalbuminuric patients serum TGF-beta levels increased at the onset of NIDDM and remained elevated throughout the disease. They did not change at the onset of IDDM, however, and started to decrease around 2 years after the onset of the disease.
Also see MOLECULAR GENETICS section.
Role in Cancer
Derynck et al. (2001) reviewed TGF-beta signaling in tumor suppression and cancer progression. Of the 3 TGFBs, TGFB1 is most frequently upregulated in tumor cells and is the focus of most studies on the role of TGFB in tumorigenesis. The autocrine and paracrine effects of TGF-beta on tumor cells and the tumor microenvironment exert both positive and negative influences on cancer development. Derynck et al. (2001) attempted to reconcile the positive and negative effects of TGF-beta in carcinogenesis.
Using a synergistic transplantation system and a chronic myeloid leukemia (CML)-like myeloproliferative disease mouse model, Naka et al. (2010) showed that Foxo3a has an essential role in the maintenance of CML leukemia-initiating cells (LIC). They found that cells with nuclear localization of Foxo3a and decreased Akt (164730) phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a-wildtype and Foxo3a-null mice showed that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, Naka et al. (2010) found that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency, and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Naka et al. (2010) concluded that their results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs.
Also see MOLECULAR GENETICS section.
Role in Camurati-Engelmann Disease
See MOLECULAR GENETICS section.
Role in Lung Disease
Munger et al. (1999) showed that the TGFB1 latency-associated peptide (LAP) is a ligand for the integrin alpha-V-beta-6 (see 193210 and 147558) and that alpha-V-beta-6-expressing cells induce spatially restricted activation of TGF-beta-1. They suggested that their finding explains why mice lacking this integrin develop exaggerated inflammation and, as they showed, are protected from pulmonary fibrosis. Pittet et al. (2001) showed that integrin alpha-V-beta-6 activates latent TGFB in the lungs and skin. They also showed that mice lacking this integrin are completely protected from pulmonary edema in a model of bleomycin-induced acute lung injury. Pharmacologic inhibition of TGFB also protected wildtype mice from pulmonary edema induced by bleomycin or E. coli endotoxin. TGFB directly increased alveolar epithelial permeability in vitro by a mechanism that involved depletion of intracellular glutathione. Pittet et al. (2001) concluded that integrin-mediated local activation of TGFB is critical to the development of pulmonary edema in acute lung injury and that blocking TGFB or its activation could be effective treatments.
Role in Obesity
Long et al. (2003) noted that increased expression and a polymorphism of TGFB1 had been associated with abdominal obesity and body mass index (BMI) in humans. They investigated the association of TGFB1 and APOE (107741) with obesity by analyzing several SNPs of each gene in 1,873 subjects from 405 white families to test for linkage or association with 4 obesity phenotypes including BMI, fat mass, percentage fat mass (PFM), and lean mass, with the latter 3 being measured by dual energy x-ray absorptiometry. A significant linkage disequilibrium (p less than 0.01) was observed between pairs of SNPs within each gene except for SNP5 and SNP6 in TGFB1 (p greater than 0.01). Within-family association was observed in the APOE gene for SNP1 and PFM (p = 0.001) and for the CGTC haplotype with both fat mass (p = 0.012) and PFM (p = 0.006). For the TGFB1 gene, within-family association was found between lean mass and SNP5 (p = 0.003), haplotype C+C (p = 0.12), and haplotype T+C (p = 0.012). Long et al. (2003) concluded that the large study size, analytical method, and inclusion of the lean mass phenotype improved the power of their study and explained discrepancies in previous studies, and that both APOE and TGFB1 are associated with obesity phenotypes in their population.
Role in Cardiac Fibrosis
Zeisberg et al. (2007) showed that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. TGFB1 induced endothelial cells to undergo EndMT, whereas bone morphogenic protein-7 (BMP7; 112267) preserved the endothelial phenotype. The systemic administration of recombinant human BMP7 significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Zeisberg et al. (2007) concluded that EndMT contributes to the progression of cardiac fibrosis and that recombinant human BMP7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
Davis et al. (2008) demonstrated that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR21 (611020). miR21 downregulates PDCD4 (608610), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in expression of mature miR21 through a posttranscriptional step, promoting the processing of primary transcripts of miR21 (pri-miR21) into precursor miR21 (pre-miR21) by the Drosha complex (608828). TGF-beta and BMP-specific SMAD signal transducers SMAD1 (601595), SMAD2 (601366), SMAD3, (603109), and SMAD5 (603110) are recruited to pri-miR21 in a complex with the RNA helicase p68 (DDX5; 180630), a component of the Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not required for this process. Thus, Davis et al. (2008) concluded that regulation of microRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signaling pathways.
Role in Marfan Syndrome
Selected manifestations of Marfan syndrome (MFS; 154700) reflect excessive signaling by the TGF-beta family of cytokines. Habashi et al. (2006) showed that aortic aneurysm in a mouse model of Marfan syndrome is associated with increased TGF-beta signaling and can be prevented by TGF-beta antagonists such as TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor (AGTR1; 106165) blocker, losartan.
Gelb (2006) discussed the mechanism by which TGF-beta interacts with the extracellular matrix and the role of fibrillin (134797), mutation in which causes Marfan syndrome.
Matt et al. (2009) found that circulating total TGFB1 levels were significantly higher in patients with Marfan syndrome than controls (p less than 0.0001), and Marfan syndrome patients treated with losartan or beta-blocker showed significantly lower total TGFB1 concentrations compared with untreated Marfan syndrome patients (p = 0.03 to 0.05). However, the authors did not observe a close correlation between circulating TGFB1 levels and aortic root size or Z scores. Matt et al. (2009) concluded that TGFB1 levels might serve as a prognostic or therapeutic marker in Marfan syndrome.
Crystal Structure
Shi et al. (2011) determined the crystal structure of pro-TGF-beta-1 at 3.05-angstrom resolution. Crystals of dimeric porcine pro-TGF-beta-1 revealed a ring-shaped complex, a novel fold for the prodomain, and showed how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between alpha-V-beta-6 integrin (see 193210) and the prodomain is insufficient for TGF-beta-1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth factor monomer at a position that can be locked by a disulfide bond. Sequences of all 33 TGF-beta family members indicated a similar prodomain fold.
Lienart et al. (2018) solved the crystal structure of GARP (137207):latent TGF-beta 1 bound to an antibody that stabilizes the complex and blocks release of active TGF-beta-1. This finding revealed how GARP exploits an unusual medley of interactions, including fold complementation by the amino terminus of TGF-beta 1, to chaperone and orient the cytokine for binding and activation by alpha-V-beta-8 integrin.
In a study of 170 pairs of female twins (average age 57.7 years), Grainger et al. (1999) showed that the concentration of active plus acid-activatable latent TGFB1 is predominantly under genetic control (heritability estimate 0.54). SSCP mapping of the TGFB1 gene promoter identified 2 single-base substitution polymorphisms. The 2 polymorphisms (G to A at position -800 bp and C to T at position -509 bp) are in linkage disequilibrium. The -509C-T polymorphism (rs1800469) was significantly associated with plasma concentration of active plus acid-activatable latent TGFB1, which explained 8.2% of the additive genetic variance in the concentration. Grainger et al. (1999) suggested, therefore, that predisposition to atherosclerosis, bone diseases, or various forms of cancer may be correlated with the presence of particular alleles at the TGFB1 locus.
The -509C-T (-1347C-T) SNP of the TGFB1 gene results in increased plasma levels of TGF-beta-1. Shah et al. (2006) demonstrated that the difference in TGFB1 levels was due to transcriptional suppression by AP1 (see 165160) binding to wildtype -1347C. In vitro and in vivo cellular studies showed that an AP1 complex containing JunD (165162) and c-Fos (164810) was recruited to the TGFB1 promoter only when the -1347C allele was present. Thus, increased TGF-beta-1 levels are associated with the -1347T allele because of the loss of negative regulation by AP1. Shah et al. (2006) also found that HIF1A (603348) bound to a site that overlaps the AP1 binding site surrounding -1347, suggesting that the 2 transcription factors compete for binding to -1347C.
African Americans (blacks) have a higher incidence and prevalence of hypertension and hypertension-associated target organ damage compared with Caucasian Americans (whites). Suthanthiran et al. (2000) explored the hypotheses that TGFB1 is hyperexpressed in hypertensives compared with normotensives and that TGFB1 overexpression is more frequent in blacks than in whites. These hypotheses were stimulated by the demonstration that TGFB1 is hyperexpressed in blacks with end-stage renal disease compared with white end-stage renal disease patients (Suthanthiran et al., 1998; Li et al., 1999) and by the biologic attributes of TGFB1, which include induction of endothelin-1 expression, stimulation of renin release, and promotion of vascular and renal disease when TGFB1 is produced in excess. Suthanthiran et al. (2000) determined TGFB1 profiles in black and white hypertensive subjects and normotensive controls and included circulating protein concentrations, mRNA steady-state levels, and codon 10 genotype. They showed that TGFB1 protein levels are highest in black hypertensives, and TGFB1 protein as well as TGFB1 mRNA levels are higher in hypertensives compared with normotensives. The proline allele at codon 10 was more frequent in blacks compared with whites, and its presence was associated with higher levels of TGFB1 mRNA and protein. The findings of Suthanthiran et al. (2000) supported the idea that TGFB1 hyperexpression is a risk factor for hypertension and hypertensive complications and provided a mechanism for the excess burden of hypertension in blacks.
Blobe et al. (2000) reviewed the role of TGFB in human disease. Many aspects of cancer involve mutations in the TGF-beta pathway. Two forms of hereditary hemorrhagic telangiectasia (HHT1, 187300; HHT2, 600376) has been shown to be caused by mutations in the genes for 2 receptors in the TGF-beta family, endoglin (ENG; 131195) and ALK1 (601284). There is also evidence that TGF-beta, when overexpressed, has a role in fibrotic disease. The authors cited the description by Awad et al. (1998) of a polymorphism of the TGFB1 gene that increases the production of TGF-beta-1 and is associated with the development of fibrotic lung disease.
Watanabe et al. (2002) identified 106 SNPs and 11 other types of variations in TGFB1 and 6 other genes: TGFBR1 (190181), TGFBR2 (190182), SMAD2 (601366), SMAD3, SMAD4 (600993), and SMAD7 (602932), all of which are part of the TGF-beta-1 signaling pathway. Watanabe et al. (2002) also estimated allele frequencies of these DNA polymorphisms among 48 Japanese individuals.
Celedon et al. (2004) performed association analysis between SNPs in the TGFB1 gene and chronic obstructive pulmonary disease (COPD; 606963) phenotypes in a family-based sample and a case-control study. Stratification by smoking status substantially improved the evidence of linkage to chromosome 19q for COPD phenotypes. Among former and current smokers in the study, there was significant evidence of linkage (lod = 3.30) between chromosome 19q and prebronchodilator (pre-BD) forced expiratory volume at 1 second (FEV1). In these families, 3 SNPs in TGFB1 were significantly associated with pre- and post-BD FEV1 (p less than 0.05). Among smokers in the COPD cases and control subjects, 3 SNPs in TGFB1 were significantly associated with COPD (p less than or equal to 0.02 in all cases). Celedon et al. (2004) concluded that chromosome 19q likely contains a genetic locus (or loci) that influences COPD through an interaction with cigarette smoking.
Shah et al. (2006) reported a comprehensive examination of function and diversity for the regulatory region of TGFB1, including an expanded promoter region and exon 1 (-2665 to +423). The authors identified strong enhancer activity for a distal promoter segment (-2665 to -2205). Ten novel polymorphisms and 14 novel alleles were identified among 38 unrelated racially diverse samples, and many of the SNPs were unique to persons of African descent. In vitro functional assays of 2 of the variants, -1287G-A (rs11466314) and -387C-T (rs11466315), showed differences in reporter gene expression.
Phillips et al. (2008) studied SNP genotypes of TGF-beta in BMPR2 (600799) mutation carriers with pulmonary hypertension (178600) and examined the age of diagnosis and penetrance of the pulmonary hypertension phenotype. BMPR2 heterozygotes with least active -509 or codon 10 TGFB1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years, respectively) than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis showed that those with less active SNPs had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay-resistant BMPR2 mutations and the least, intermediate, and most active -509 TGFB1 SNP phenotypes had penetrances of 33%, 72%, and 80%, respectively (P = 0.003), whereas those with 0-1, 2, or 3-4 active SNP alleles had penetrances of 33%, 72%, and 75% (P = 0.005). Phillips et al. (2008) concluded that the TGFB1 SNPs studied modulate age at diagnosis and penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFB/BMP signaling imbalance. The authors considered this modulation an example of synergistic heterozygosity.
Camurati-Engelmann Disease
Camurati-Engelmann disease (CAEND; 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperostosis and sclerosis of the diaphyses of long bones. This disorder was mapped to 19q13.1-q13.3, making TGFB1 a candidate for the site of the causative mutations. Kinoshita et al. (2000) screened the TGFB1 gene for mutations in affected members of 7 unrelated Japanese families and 2 families of European descent. They detected 3 different heterozygous missense mutations in exon 4, near the carboxy terminus of the latency-associated peptide (LAP), in all 9 families examined. All mutation sites in the 9 CED patients were located either at (C225) or near (R218) the S-S bonds in LAP, suggesting the importance of this region in activating TGF-beta-1 in the bone matrix. Noteworthy, arginine at 218 and cysteine at 225 are highly conserved from chicken to human, and hydropathy plots indicated that all 3 mutations affect the dimerization of LAP, consequently altering the conformation of the domain structure.
Janssens et al. (2000) also reported 4 different mutations of the TGFB1 gene in 6 families with Camurati-Engelmann disease.
Campos-Xavier et al. (2001) stated that 5 mutations in the TGFB1 gene had been identified in 21 families with CED. In 1 Australian family and 6 European families with CED, they found 3 of these mutations, R218H (190180.0002) in 1 family, R218C (190180.0003) in 3 families, and C225R (190180.0001) in 3 families, which had previously been observed in families of Japanese and Israeli origin. The R218C mutation appeared to be the most prevalent worldwide, having been found in 17 of 28 reported families. Campos-Xavier et al. (2001) found no obvious correlation between the nature of the mutations and the severity of the clinical manifestations, but observed a marked intrafamilial clinical variability, supporting incomplete penetrance of CED.
Kinoshita et al. (2000) identified 3 mutations in the TGFB1 gene in patients with CED. They commented that studies of the role of TGF-beta in modeling and/or remodeling bone tissue were conflicting. Whether the 3 mutations they observed result in hyperactivation of TGF-beta-1 or its early degradation in vivo leading to insufficient signal transduction remained to be investigated.
Janssens et al. (2003) stated that a total of 7 different mutations in TGFB1 had been found as the cause of CED. They investigated the effects of 5 of these on the functioning of TGF-beta-1 in vitro. A luciferase reporter assay specific for TGF-beta-induced transcriptional response showed that all 5 mutations increased TGF-beta-1 activity. In 3 of the mutations, this effect was caused by an increase in active TGF-beta-1 in the medium of the transfected cells. The other 2 mutations had a profound effect on secretion; a decreased amount of TGF-beta-1 was secreted, but increased luciferase activity showed that an aberrant intracellular accumulation of gene product could initiate an enhanced transcriptional response, suggesting the existence of an alternative signaling pathway. The data indicated that mutations in the signal peptide and latency-associated peptide facilitate TGFB1 signaling, thus causing Camurati-Engelmann disease.
Kinoshita et al. (2004) performed haplotype analysis of 13 unrelated CED patients and found that at least 9 independent mutation events had occurred (see, e.g., 190180.0005-190180.0006). They pointed out that there are at least 3 'accumulation sites' of mutations in the TGFB1 gene: amino acid positions 218, 223, and 225. The cysteine residues at these positions serve as disulfide bonds between 2 LAP molecules and contribute to their dimerization.
Inflammatory Bowel Disease, Immunodeficiency, and Encephalopathy
In 3 patients from 2 unrelated families with inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE; 618213), Kotlarz et al. (2018) identified homozygous or compound heterozygous missense mutations in the TGFB1 gene (190180.0008-190180.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies in HEK293 cells showed that the mutations resulted in reduced levels of secreted TGFB1 and reduced downstream signaling compared to controls, consistent with a loss of function. Colonic biopsy from 1 patient showed reduced levels of phosphorylated SMAD2 (601366)/SMAD3 (603109) in lamina propria mononuclear cells. Reduced levels of phosphorylated SMAD2/3 were also seen in mononuclear cells from an unrelated patient with Crohn disease (see 266600), suggesting a common pathophysiology.
TGF-beta plays an important role in wound healing. A number of pathologic conditions, such as idiopathic pulmonary fibrosis, scleroderma, and keloids, which share the characteristic of fibrosis, are associated with increased TGF-beta-1 expression. To evaluate the role of TGF-beta-1 in the pathogenesis of fibrosis, Clouthier et al. (1997) used a transgenic approach. They targeted the expression of a constitutively active TGF-beta-1 molecule to liver, kidney, and white and brown adipose tissue using the regulatory sequences of the rat phosphoenolpyruvate carboxykinase gene (261650). In multiple lines, targeted expression of the transgene caused severe fibrotic disease. Fibrosis of the liver occurred with varying degrees in severity depending upon the level of expression of the TGFB1 gene. Overexpression of the transgene in kidney also resulted in fibrosis and glomerular disease, eventually leading to complete loss of renal function. Severe obstructive uropathy (hydronephrosis) was also observed in a number of animals. Expression in adipose tissue resulted in a dramatic reduction in total body white adipose tissue and a marked, though less severe, reduction in brown adipose tissue, producing a lipodystrophy-like syndrome. Introduction of the transgene into the ob/ob background (see 164160) suppressed the obesity characteristic of this mutation; however, transgenic mutant mice developed severe hepato- and splenomegaly. Clouthier et al. (1997) noted that the family of rare conditions known collectively as the lipodystrophies (151660, 269700) are accompanied in almost all forms by other abnormalities, including fatty liver and cardiomegaly. Metabolic and endocrine abnormalities include either mild or severe insulin resistance, hypertriglyceridemia, and a hypermetabolic state.
Crawford et al. (1998) showed that thrombospondin-1 (188060) is responsible for a significant proportion of the activation of TGFB1 in vivo. Histologic abnormalities in young Tgfb1-null and thrombospondin-1-null mice were strikingly similar in 9 organ systems. Lung and pancreas pathologies similar to those observed in Tgfb1-null animals could be induced in wildtype pups by systemic treatment with a peptide that blocked the activation of TGFB1 by thrombospondin-1. Although these organs produced little active TGFB1 in thrombospondin-1-null mice, when pups were treated with a peptide derived from thrombospondin-1 that could activate TGFB1, active cytokine was detected in situ, and the lung and pancreatic abnormalities reverted toward wildtype.
Wyss-Coray et al. (1997) found that aged transgenic mice with increased astrocytic expression of TGFB1 showed increased deposition of the beta-amyloid precursor protein (APP; 104760) in cerebral blood vessels and meninges. Cerebral vessel amyloid deposition was further increased in transgenic mice overexpressing APP, similar to the vascular changes seen in patients with Alzheimer disease (AD; 104300) and cerebral amyloid angiopathy (CAA). Postmortem analysis of 15 AD brains showed increased TGFB1 immunoreactivity and increased TGFB1 mRNA, which correlated with beta-amyloid deposition in damaged cerebral blood vessels of patients with AD and CAA compared to AD patients without CAA or normal controls. Wyss-Coray et al. (1997) concluded that glial overexpression of TGFB1 may promote the deposition of cerebral vascular beta-amyloid in AD-related amyloidosis.
TGFB1, a key regulator of the brain's responses to injury and inflammation, has been implicated in amyloid-beta deposition in vivo. Wyss-Coray et al. (2001) demonstrated that a modest increase in astroglial TGFB1 production in aged transgenic mice expressing the human APP (Games et al., 1995) results in a 3-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall amyloid-beta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing human APP and TGFB1, amyloid-beta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of Alzheimer disease, amyloid-beta immunoreactivity associated with parenchymal plaques was inversely correlated with amyloid-beta in blood vessels and cortical TGFB1 mRNA levels. The reduction of parenchymal plaques in APP/TGFB1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGFB1 stimulated amyloid-beta clearance in microglial cell cultures. Wyss-Coray et al. (2001) concluded that TGFB1 is an important modifier of amyloid deposition in vivo and indicate that TGFB1 might promote microglial processes that inhibit the accumulation of amyloid-beta in the brain parenchyma.
Ikuno and Kazlauskas (2002) studied the role of TGFB1 in the tractional retinal detachments of proliferative vitreoretinopathy in rabbits. Their results showed that vitreous promoted cellular contraction, that TGFB1 was the major factor responsible, and that at least a portion of the TGFB1-dependent contraction proceeded through platelet-derived growth factor receptor-alpha (PDGFRA; 173490). They concluded that PDGFRA is responsible for mediating cellular contraction of multiple growth factors: TGFB1 and members of the PDGF family.
Thyagarajan et al. (2001) developed transgenic mice that overexpressed Tgfb1 predominantly in odontoblasts. The transgene for targeted expression was constructed by fusing the Dspp (125485) upstream regulatory sequence to an active porcine Tgfb1 cDNA. The teeth of transgenic mice expressing this construct showed a significant reduction in tooth mineralization, defective dentin formation, and a relatively high branching of dentinal tubules. Dentin extracellular matrix components were increased and deposited abnormally in the dental pulp. Expression of Dspp was significantly downregulated.
A subgroup of individuals with Marfan syndrome (154700), an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (FBN1; 134797), have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax). Neptune et al. (2003) showed that mice deficient in fibrillin-1 have marked dysregulation of TGF-beta activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta by means of a TGF-beta-neutralizing antibody attenuated apoptosis and rescued alveolar septation in vivo. These data indicated that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease. Kaartinen and Warburton (2003) discussed the general implications of the finding that fibrillin controls TGF-beta activation.
Ng et al. (2004) examined mitral valves from Fbn1-null mice and found postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-beta activation and signaling. TGF-beta antagonism in vivo rescued the valve phenotype. Expression analyses identified increased expression of numerous TGF-beta-related genes that regulate cell proliferation and survival. Ng et al. (2004) suggested that TGF-beta is a mediator of myxomatous mitral valve disease.
In Fbn1-deficient mice, Cohn et al. (2007) demonstrated that increased TGF-beta activity resulted in failed muscle regeneration by inhibition of satellite cell proliferation and differentiation. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the AGTR1 (106165) blocker losartan normalized muscle architecture, repair, and function in vivo. In dystrophin (300377)-deficient mdx mice, a model of Duchenne muscular dystrophy (310200), Cohn et al. (2007) also demonstrated TGF-beta-induced failure of muscle regeneration and a similar therapeutic response.
Matt et al. (2009) found that circulating total Tgfb1 levels in Fbn1-deficient mice increased with age and were elevated compared to age-matched wildtype mice. Losartan-treated Fbn1-null mice had lower total Tgfb1 levels compared to age-matched Fbn1-null mice treated with placebo, and circulating total Tgfb1 levels were indistinguishable from those of age-matched wildtype mice. In addition, Matt et al. (2009) observed a correlation between circulating Tgfb1 levels and aortic root diameters in Fbn1-null and wildtype mice (p = 0.002).
Through a global analysis of pulmonary gene expression in the lungs of mice lacking integrin beta-6 (ITGB6; 147558), Kaminski et al. (2000) identified a marked induction of macrophage metalloelastase (MMP12; 601046), a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema. Morris et al. (2003) demonstrated that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta-6 integrin unit that support TGFB activation, or by the loss of MMP12. Furthermore, Morris et al. (2003) showed that the effects of ITGB6 deletion are overcome by simultaneous transgenic expression of active TGFB1. Morris et al. (2003) concluded that they had uncovered a pathway in which the loss of integrin-mediated activation of latent TGFB causes age-dependent pulmonary emphysema through alterations of macrophage MMP12 expression. Furthermore, they showed that a functional alteration in the TGFB activation pathway affects susceptibility to this disease.
Using transgenic mouse models, Siegel et al. (2003) examined the influence of TGF-beta signaling on Neu (164870)-induced mammary tumorigenesis and metastases. They generated mice expressing an activated TGF-beta type I receptor (TGFBR1; 190181) or dominant-negative TGF-beta type II receptor (TGFBR2; 190182) under control of the mouse mammary tumor virus promoter. When crossed with mice expressing activated forms of the Neu receptor tyrosine kinase that selectively couple to the Grb2 (108355) or Shc (600560) signaling pathways, the activated type I receptor increased the latency of mammary tumor formation but also enhanced the frequency of extravascular lung metastasis. Conversely, expression of the dominant-negative type II receptor decreased the latency of Neu-induced mammary tumor formation while significantly reducing the incidence of extravascular lung metastases. These observations argued that TGF-beta can promote the formation of lung metastases while impairing Neu-induced tumor growth and suggested that extravasation of breast cancer cells from pulmonary vessels is a point of action of TGF-beta in the metastatic process.
Sancho et al. (2003) analyzed a model of collagen-induced arthritis in wildtype and Cd69 antigen (107273)-deficient mice and found that levels of TGFB1 and TGFB2, which act as protective agents in collagen-induced arthritis, were reduced in Cd69-null mice inflammatory foci, correlating with an increase in proinflammatory cytokines. Local injection of blocking anti-TGF antibodies increased arthritis severity and proinflammatory cytokine mRNA levels in Cd69 wildtype but not null mice. Sancho et al. (2003) concluded that CD69 is a negative modulator of autoimmune reactivity and inflammation through the synthesis of TGFB1, a cytokine that in turn downregulates the production of various proinflammatory mediators.
Tang et al. (2003) identified a potent modifier locus on chromosome 1 (lod = 10.5), Tgfbkm2(129), that contributed over 90% of the genetic component determining survival to birth (STB) of Tgfb1 -/- embryos in crosses between C57 and 129 mice. Tgfb1 -/- STB also depended on maternal effects. Fetal genotype and maternal factors interacted to prevent Tgfb1 -/- embryonic death due to defective yolk sac angiogenesis. C57 or C57/129 F1 mothers supported high Tgfb1 -/- STB rates, whereas 129 mothers did not. Strain differences in circulating maternal TGF-beta-1 levels were excluded as the cause of this directional complementation; however, strong genetic support was evident for the involvement of maternal STB alleles of mitochondrial or imprinted genes that are only expressed when passed through the female lineage.
Brionne et al. (2003) studied a mouse strain that survived to about 3 weeks of age in the absence of Tgfb1. These mice showed increased numbers of apoptotic neurons, reduced neocortical presynaptic integrity, reduced laminin (see 156225) expression, and widespread microgliosis. Cultured primary neurons lacking Tgfb1 had reduced survival compared with wildtype controls. Heterozygous knockout mice had normal life spans, but they showed increased susceptibility to excitotoxic injury and neurodegeneration. Transgenic overproduction of Tgfb1 prevented degeneration after excitotoxic injury. Brionne et al. (2003) concluded that TGFB1 has a nonredundant function in maintaining neuronal integrity and survival of central nervous system neurons and in regulating microglial activation.
Gao et al. (2004) generated mice with T cell-specific blockade of Tgfb1 signaling and found that the mice were completely insensitive to the bone-sparing effect of estrogen. This insensitivity was accompanied by upregulation of Ifng, which in turn led to increased T-cell activation and T-cell Tnf production. Overexpression of Tgfb1 in vivo prevented ovariectomy-induced bone loss. Gao et al. (2004) concluded that estrogen prevents bone loss through a TGFB-dependent mechanism and that TGFB signaling in T cells preserves bone homeostasis by blunting T-cell activation.
TGFB1 is a potent keratinocyte growth inhibitor that is overexpressed in keratinocytes in certain inflammatory skin diseases. Li et al. (2004) found that transgenic mice expressing human TGFB1 in epidermis using a keratin-5 (KRT5; 148040) promoter developed inflammatory skin lesions, with gross appearance of psoriasis (see 177900)-like plaques, generalized scaly erythema, and Koebner phenomenon, in which a mechanical trauma induces or exacerbates psoriatic lesions. The lesions were characterized by epidermal hyperproliferation, massive infiltration of neutrophils, T lymphocytes, and macrophages to the epidermis and superficial dermis, subcorneal microabscesses, basement membrane degradation, and angiogenesis. Transgenic skin exhibited multiple molecular changes that typically occur in T helper-1 (Th1) cell inflammatory skin disorders, such as psoriasis. Further analysis revealed enhanced SMAD signaling in transgenic epidermis and dermis. Li et al. (2004) concluded that pathologic condition-induced TGFB1 overexpression in skin may synergize with or induce molecules required for the development of Th1 inflammatory skin disorders.
Wurdak et al. (2005) inactivated the Tgfb gene in mouse neural crest stem cells by targeted deletion. Mutants were recovered at the expected mendelian frequency until embryonic day 18.5, but they died perinatally, displaying multiple developmental defects, including mid/hindbrain abnormalities. The mutant mice also showed several malformations seen in patients with DiGeorge syndrome (188400), including malformations of cranial bones and cartilage, cleft palate, hypoplastic parathyroid and thymus glands, ventricular septal defect, truncus arteriosus, and abnormal patterning of the arteries arising from the aortic arch. Wurdak et al. (2005) found that Tgfb signaling in mouse neural crest cells was necessary and sufficient for phosphorylation of Crkl (602007), a signal adaptor implicated in the development of DiGeorge syndrome. Wurdak et al. (2005) concluded that TGFB signaling may play a role in the etiology of DiGeorge syndrome.
Han et al. (2005) found that human skin cancers frequently overexpress TGFB1 but exhibit decreased expression of the TGF-beta type II receptor (TGFBR2; 190182). In transgenic mouse models in which Tgfb1 expression could be induced at specific stages of skin carcinogenesis in tumor epithelia expressing a dominant-negative Tgfbr2, they observed that late-stage Tgfb1 overexpression in chemically induced skin papillomas did not exert a tumor-suppressive effect and that dominant-negative Tgfbr2 expression selectively blocked Tgfb1-mediated epithelial-to-mesenchymal transition but cooperated with Tgfb1 for tumor invasion. Han et al. (2005) concluded that TGFB1 induces epithelial-to-mesenchymal transition and invasion via distinct mechanisms: TGFB1-mediated epithelial-to-mesenchymal transition requires functional TGFBR, whereas TGFB1-mediated tumor invasion cooperates with reduced TGFBR2 signaling in tumor epithelia.
Mao et al. (2006) identified a mouse skin tumor susceptibility locus, termed Skts14, containing the Tgfb1 gene on proximal chromosome 7. Different polymorphic alleles at this locus resulting in differential Tgfb1 gene expression altered skin tumor susceptibility. Moreover, fine genetic mapping of different mouse strains showed that allelic variants at the Skts14 locus interacted with the Skts15 tumor modifier locus on chromosome 12 to drive papilloma susceptibility, indicating complex genetic interactions in determining disease outcome.
Mangan et al. (2006) showed that exogenous Tgfb induced development of proinflammatory Il17-producing T cells (Th17 cells) in Il12b (161561) -/- mice, whose antigen-presenting cells produce neither Il12 or Il23. In Ifng -/- T cells, Tgfb induced expression of Il23r (607562), conferring Il23 responsiveness for Th17 cell development. Challenge of Il12b -/- mice or Il23a (605580) -/- mice with a natural rodent pathogen, Citrobacter rodentium, resulted in failure to clear infection and death. In contrast to Il12b -/- mice, Il23a -/- mice did not show impaired induction of an Il17 response. Histopathologic and flow cytometric analysis demonstrated that intestinal tissue was enriched in Th17 cells in wildtype mice, but not in Tgfb -/- mice; Tgfb +/- mice had intermediate levels of Th17 cells. Activation of naive T cells with Tgfb resulted in expression of both intracellular Il17 and Foxp3, a transcription factor associated with Treg cells. Addition of Il6 (147620), however, nearly extinguished the Foxp3-positive cells. Mangan et al. (2006) concluded that TGFB plays a dual role in T-cell differentiation by directing distinct populations of FOXP3-positive Treg cells and Th17 cells, contingent upon the inflammatory cytokine environment.
Using mice with green fluorescent protein introduced into the endogenous Foxp3 locus, Bettelli et al. (2006) found that Il6 completely inhibited generation of Foxp3-positive Treg cells induced by Tgfb. The combination of Il6 together with Tgfb induced differentiation of pathogenic Th17 cells from naive T cells. Bettelli et al. (2006) proposed that, in the steady state or in the absence of an inflammatory insult, TGFB suppresses induction of effector cells, such as Th1, Th2, or Th17 cells, and induces FOXP3-positive Treg cells that maintain self tolerance.
Yang et al. (2007) found that homozygous mutant Tgfb1 mice in which the integrin-binding site is inactivated (RGD changed to RGE) show normal Tgfb1 gene expression, function, processing, and secretion, but display features similar to those observed in Tgfb1 knockout mice, i.e., vasculogenesis defects, multiorgan inflammation, and lack of Langerhans cells.
Using in vitro and in vivo models, Tang et al. (2009) demonstrated that active TGFB1 released during bone resorption coordinates bone formation by inducing migration of bone mesenchymal stem cells to the bone resorptive sites, and that this process is mediated through a SMAD (see 601595) signaling pathway. Tang et al. (2009) generated mice carrying point mutations previously identified in patients with CED and observed the typical progressive diaphyseal dysplasia seen in the human disease, with high levels of active TGFB1 in the bone marrow. Treatment with a TGFB1 receptor inhibitor partially rescued the uncoupled bone remodeling and prevented fractures.
Gupta et al. (2006) retracted their paper describing the identification of a microRNA in the latency-associated transcript (Lat) of herpes simplex virus (HSV)-1 (miR-Lat) that targets TGFB and SMAD3 (603109) via sequences in their 3-prime UTRs that show partial homology to miR-Lat.
The article in which Dong et al. (2002) suggested that alterations in the SMAD pathway, including marked SMAD7 deficiency and SMAD3 upregulation, may be responsible for TGFB hyperresponsiveness observed in scleroderma (181750) was retracted because some of the elements in figure 3 may have been fabricated.
In a Japanese patient with Camurati-Engelmann disease (CAEND; 131300), Kinoshita et al. (2000) found a heterozygous c.673T-C transition in the TGFB1 gene resulting in a cys225-to-arg (C225R) missense mutation.
Janssens et al. (2000) found the C225R mutation in a family of European descent.
Saito et al. (2001) demonstrated that the C225R mutation causes the instability of the LAP homodimer and consequently leads to the activation of a constitutively active form of TGF-beta-1 and increased proliferation of osteoblasts.
In affected members of 2 Japanese families with Camurati-Engelmann disease (CAEND; 131300), Kinoshita et al. (2000) found a heterozygous c.653G-A transition in the TGFB1 gene resulting in an arg218-to-his (R218H) missense amino acid substitution.
In 2 families of European descent, and 3 Japanese families, with Camurati-Engelmann disease (CAEND; 131300), Kinoshita et al. (2000) found that affected individuals had a heterozygous c.652C-T transition in the TGFB1 gene resulting in an arg218-to-cys (R218C) missense mutation.
Janssens et al. (2000) found this mutation in 3 European families.
Kinoshita et al. (2004) stated that R218C was the most frequent mutation among the 40 reported families with CED that had been analyzed for mutation in the TGFB1 gene. The arginine residue at codon 218 is evolutionarily conserved among species and also affects the dimerization of the TGFB1 latency-associated peptide (LAP).
McGowan et al. (2003) studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from 3 related CED patients harboring the R218C mutation, in comparison with 1 family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold and bone resorption approximately 10-fold in CED patients, and the increase in osteoclast formation was inhibited by soluble TGF-beta type II receptor (190182). Total serum TGFB1 levels were similar in affected and unaffected subjects, but concentrations of active TGFB1 in conditioned medium of osteoclast cultures was higher in the 3 CED patients than in the unaffected family member. The authors concluded that the R218C mutation increases TGFB1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity was consistent with clinical reports that showed biochemical evidence of increased bone resorption as well as bone formation in CED.
In a European family, Janssens et al. (2000) found a heterozygous tyr81-to-his (Y81H) substitution in the TGFB1 gene as the cause of Camurati-Engelmann disease (CAEND; 131300).
In affected members of a Japanese family with Camurati-Engelmann disease (CAEND; 131300), Kinoshita et al. (2004) identified a heterozygous c.667T-C transition in exon 4 of the TGFB1 gene, resulting in a cys223-to-arg (C223R) mutation.
In affected members of a Japanese family with Camurati-Engelmann disease (CAEND; 131300), Kinoshita et al. (2004) identified a heterozygous c.667T-G transversion in exon 4 of the TGFB1 gene, resulting in a cys223-to-gly (C223G) mutation.
Cystic Fibrosis Lung Disease, Modifier of
Drumm et al. (2005) found that patients with cystic fibrosis (CF; 219700) and homozygosity for the common phe508del mutation (602421.0001) had an increased risk of severe pulmonary disease (odds ratio = 2.2) if they were also homozygous for C at nucleotide 29 of the TGFB1 gene, corresponding to a change in codon 10. The authors referred to this genotype as codon 10 CC and the SNP as C29T. A change from the more common base at this position, T, to C results in an amino acid change from leucine to proline (L10P) (Knowles, 2005).
In a study of 1,019 Canadian pediatric CF patients, Dorfman et al. (2008) found a significant association between earlier age of first P. aeruginosa infection and MBL2 (154545) deficiency (onset at 4.4, 7.0, and 8.0 years for low, intermediate, and high MBL2 groups according to MBL2 genotype, respectively; p = 0.0003). This effect was amplified in patients with the high-producing genotypes of TGFB1, including variant C of codon 10. MBL2 deficiency was also associated with more rapid decline of pulmonary function, most significantly in those homozygous for the high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1 affected the modulation of age of onset by MBL2, there was no significant direct impact of TFGB1 codon 10 genotypes alone. The findings provided evidence for a gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGFB1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
In a study of 472 CF patient/parent trios, Bremer et al. (2008) found that a 3-SNP haplotype (CTC) composed of the -509 SNP (rs1800469) C allele, the codon 10 SNP (rs1982073) T allele, and a 3-prime SNP (rs8179181) C allele was highly associated with increased lung function in patients grouped by CFTR genotype. Bremer et al. (2008) concluded that TGFB1 is a modifier of CF lung disease, with a beneficial effect of certain variants on the pulmonary phenotype.
Breast Cancer, Invasive, Susceptibility to
In studies using data contributed to the Breast Cancer Association Consortium (BCAC), Cox et al. (2007) found evidence for a significant dose-dependent association of the proline-encoding allele of the L10P SNP (rs1982073) with increased risk of invasive breast cancer (see 114480) based on analyses of data from 11 studies comprising 12,946 cases and 15,109 controls. Odds ratios of 1.07 and 1.16 were observed for heterozygotes and rare homozygotes, respectively, compared with common homozygotes. Cox et al. (2007) noted that the proline variant has been associated with higher circulating levels of acid-activatable TGF-beta and increased rates of TGF-beta secretion in in vitro transfection experiments. The significant association of the proline variant was confined to individuals with progesterone receptor (607311)-negative tumors (P = 0.017).
In an 11-year-old boy (patient 1), born of unrelated parents from Malaysia, with inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE; 618213), Kotlarz et al. (2018) identified compound heterozygous missense mutations in the TGFB1 gene: a c.328C-T transition (c.328C-T, ENST00000221930.5), resulting in an arg110-to-cys (R110C) substitution in the latency-associated peptide (LAP) domain, and a c.1159T-C transition, resulting in a cys387-to-arg (C387R; 190180.0009) substitution in the mature growth factor domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Molecular modeling predicted that the R110C mutation could alter the interaction between 2 functional elements of the protein and that the C387R mutation could affect folding or stability of the TGFB1 growth factor domain. In vitro functional expression studies in HEK293 cells showed that the R110C mutation resulted in reduced levels of secreted TGFB1 and reduced downstream signaling compared to controls. Cells transfected with the C387R mutation had no detectable secreted TGFB1 and no downstream signaling activity, consistent with a loss of function. Colonic biopsy from the patient showed reduced levels of phosphorylated SMAD2 (601366)/SMAD3 (603109) in lamina propria mononuclear cells. Reduced levels of phosphorylated SMAD2/3 were also seen in mononuclear cells from an unrelated patient with Crohn disease, suggesting a common pathophysiology.
For discussion of the c.1159T-C transition (c.1159T-C, ENST00000221930.5) in the TGFB1 gene, resulting in a cys387-to-arg (C387R) substitution, that was found in compound heterozygous state in a patient with inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE; 618213), by Kotlarz et al. (2018), see 190180.0008.
In 2 sibs (patients 2 and 3), born of consanguineous Pakistani parents, with inflammatory bowel disease, immunodeficiency, and encephalopathy (IBDIMDE; 618213), Kotlarz et al. (2018) identified a homozygous c.133C-T transition (c.133C-T, ENST00000221930.5) in the TGFB1 gene, resulting in an arg45-to-cys (R45C) substitution in the LAP domain. Molecular modeling predicted that the mutation could alter the interaction between 2 functional elements of the protein. In vitro functional expression studies in HEK293 cells showed that the mutation resulted in reduced levels of secreted TGFB1 and reduced downstream signaling compared to controls. The findings were consistent with a loss-of-function effect.
Awad, M. R., El-Gamel, A., Hasleton, P., Turner, D. M., Sinnott, P. J., Hutchinson, I. V. Genotypic variation in the transforming growth factor-beta-1 gene: association with transforming growth factor-beta-1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 66: 1014-1020, 1998. [PubMed: 9808485] [Full Text: https://doi.org/10.1097/00007890-199810270-00009]
Azar, S. T., Salti, I., Zantout, M. S., Major, S. Alterations in plasma transforming growth factor beta in normoalbuminuric type 1 and type 2 diabetic patients. J. Clin. Endocr. Metab. 85: 4680-4682, 2000. [PubMed: 11134127] [Full Text: https://doi.org/10.1210/jcem.85.12.7073]
Bernasconi, P., Torchiana, E., Confalonieri, P., Brugnoni, R., Barresi, R., Mora, M., Conelio, F., Morandi, L., Mantegazza, R. Expression of transforming growth factor-beta-1 in dystrophic patient muscles correlates with fibrosis: pathogenetic role of a fibrogenic cytokine. J. Clin. Invest. 96: 1137-1144, 1995. [PubMed: 7635950] [Full Text: https://doi.org/10.1172/JCI118101]
Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., Kuchroo, V. K. Reciprocal developmental pathways for the generation of pathogenic effector T(H)17 and regulatory T cells. Nature 441: 235-238, 2006. [PubMed: 16648838] [Full Text: https://doi.org/10.1038/nature04753]
Blanchette, F., Day, R., Dong, W., Laprise, M.-H., Dubois, C. M. TGF-beta-1 regulates gene expression of its own converting enzyme furin. J. Clin. Invest. 99: 1974-1983, 1997. [PubMed: 9109442] [Full Text: https://doi.org/10.1172/JCI119365]
Blobe, G. C., Schiemann, W. P., Lodish, H. F. Role of transforming growth factor beta in human disease. New Eng. J. Med. 342: 1350-1358, 2000. [PubMed: 10793168] [Full Text: https://doi.org/10.1056/NEJM200005043421807]
Border, W. A., Noble, N. A. Transforming growth factor beta in tissue fibrosis. New Eng. J. Med. 331: 1286-1292, 1994. [PubMed: 7935686] [Full Text: https://doi.org/10.1056/NEJM199411103311907]
Border, W. A., Noble, N. A. Fibrosis linked to TGF-beta in yet another disease. (Editorial) J. Clin. Invest. 96: 655-656, 1995. [PubMed: 7635957] [Full Text: https://doi.org/10.1172/JCI118107]
Bremer, L. A., Blackman, S. M., Vanscoy, L. L., McDougal, K. E., Bowers, A., Naughton, K. M., Cutler, D. J., Cutting, G. R. Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. Hum. Molec. Genet. 17: 2228-2237, 2008. [PubMed: 18424453] [Full Text: https://doi.org/10.1093/hmg/ddn123]
Brionne, T. C., Tesseur, I., Masliah, E., Wyss-Coray, T. Loss of TGF-beta-1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 40: 1133-1145, 2003. [PubMed: 14687548] [Full Text: https://doi.org/10.1016/s0896-6273(03)00766-9]
Campos-Xavier, A. B., Saraiva, J. M., Savarirayan, R., Verloes, A., Feingold, J., Faivre, L., Munnich, A., Le Merrer, M., Cormier-Daire, V. Phenotypic variability at the TGF-beta-1 locus in Camurati-Engelmann disease. Hum. Genet. 109: 653-658, 2001. [PubMed: 11810278] [Full Text: https://doi.org/10.1007/s00439-001-0644-8]
Casetti, R., Agrati, C., Wallace, M., Sacchi, A., Martini, F., Martino, A., Rinaldi, A., Malkovsky, M. Cutting edge: TGF-beta-1 and IL-15 induce FOXP3(+) gamma-delta regulatory T cells in the presence of antigen stimulation. J. Immun. 183: 3574-3577, 2009. [PubMed: 19710458] [Full Text: https://doi.org/10.4049/jimmunol.0901334]
Celedon, J. C., Lange, C., Raby, B. A., Litonjua, A. A., Palmer, L. J., DeMeo, D. L., Reilly, J. J., Kwiatkowski, D. J., Chapman, H. A., Laird, N., Sylvia, J. S., Hernandez, M., Speizer, F. E., Weiss, S. T., Silverman, E. K. The transforming growth factor-beta-1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum. Molec. Genet. 13: 1649-1656, 2004. [PubMed: 15175276] [Full Text: https://doi.org/10.1093/hmg/ddh171]
Chen, S., Iglesias-de la Cruz, M. C., Jim, B., Hong, S. W., Isono, M., Ziyadeh, F. N. Reversibility of established diabetic glomerulopathy by anti-TGF-beta antibodies in dbldb mice. Biochem. Biophys. Res. Commun. 300: 16-22, 2003. [PubMed: 12480514] [Full Text: https://doi.org/10.1016/s0006-291x(02)02708-0]
Clouthier, D. E., Comerford, S. A., Hammer, R. E. Hepatic fibrosis, glomerulosclerosis, and lipodystrophy-like PEPCK-TGF-beta-1 transgenic mice. J. Clin. Invest. 100: 2697-2713, 1997. [PubMed: 9389733] [Full Text: https://doi.org/10.1172/JCI119815]
Cohn, R. D., van Erp, C., Habashi, J. P., Soleimani, A. A., Klein, E. C., Lisi, M. T., Gamradt, M., ap Rhys, C. M., Holm, T. M., Loeys, B. L., Ramirez, F., Judge, D. P., Ward, C. W., Dietz, H. C. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nature Med. 13: 204-210, 2007. Note: Erratum: Nature Med. 13: 511 only, 2007. [PubMed: 17237794] [Full Text: https://doi.org/10.1038/nm1536]
Cordenonsi, M., Montagner, M., Adorno, M., Zacchigna, L., Martello, G., Mamidi, A., Soligo, S., Dupont, S., Piccolo, S. Integration TGF-beta and Ras/MAPK signaling through p53 phosphorylation. Science 315: 840-843, 2007. [PubMed: 17234915] [Full Text: https://doi.org/10.1126/science.1135961]
Cox, A., Dunning, A. M., Garcia-Closas, M., Balasubramanian, S., Reed, M. W. R., Pooley, K. A., Scollen, S., Baynes, C., Ponder, B. A. J., Chanock, S., Lissowska, J., Brinton, L., and 67 others. A common coding variant in CASP8 is associated with breast cancer risk. Nature Genet. 39: 352-358, 2007. Note: Erratum: Nature Genet. 39: 688 only, 2007. [PubMed: 17293864] [Full Text: https://doi.org/10.1038/ng1981]
Crawford, S. E., Stellmach, V., Murphy-Ullrich, J. E., Ribeiro, S. M. F., Lawler, J., Hynes, R. O., Boivin, G. P., Bouck, N. Thrombospondin-1 is a major activator of TGF-beta-1 in vivo. Cell 93: 1159-1170, 1998. [PubMed: 9657149] [Full Text: https://doi.org/10.1016/s0092-8674(00)81460-9]
Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454: 56-61, 2008. [PubMed: 18548003] [Full Text: https://doi.org/10.1038/nature07086]
Derynck, R., Akhurst, R. J., Balmain, A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genet. 29: 117-129, 2001. Note: Erratum: Nature Genet. 29: 351 only, 2001. [PubMed: 11586292] [Full Text: https://doi.org/10.1038/ng1001-117]
Derynck, R., Jarrett, J. A., Chen, E. Y., Eaton, D. H., Bell, J. R., Assoian, R. K., Roberts, A. B., Sporn, M. B., Goeddel, D. V. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature 316: 701-705, 1985. [PubMed: 3861940] [Full Text: https://doi.org/10.1038/316701a0]
Derynck, R., Rhee, L., Chen, E. Y., Van Tilburg, A. Intron-exon structure of the human transforming growth factor-beta precursor gene. Nucleic Acids Res. 15: 3188-3189, 1987. [PubMed: 3470709] [Full Text: https://doi.org/10.1093/nar/15.7.3188]
Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A. Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci. Genomics 6: 505-520, 1990. [PubMed: 1970330] [Full Text: https://doi.org/10.1016/0888-7543(90)90480-i]
Dong, C., Zhu, S., Wang, T., Yoon, W., Li, Z., Alvarez, R. J., ten Dijke, P., White, B., Wigley, F. M., Goldschmidt-Clermont, P. J. Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc. Nat. Acad. Sci. 99: 3908-3913, 2002. Note: Retraction: Proc. Nat. Acad. Sci. 113: E2208, 2016. [PubMed: 11904440] [Full Text: https://doi.org/10.1073/pnas.062010399]
Dorfman, R., Sandford, A., Taylor, C., Huang, B., Frangolias, D., Wang, Y., Sang, R., Pereira, L., Sun, L., Berthiaume, Y., Tsue, L.-C., Pare, P. D., Durie, P., Corey, M., Zielenski, J. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J. Clin. Invest. 118: 1040-1049, 2008. [PubMed: 18292811] [Full Text: https://doi.org/10.1172/JCI33754]
Drumm, M. L., Konstan, M. W., Schluchter, M. D., Handler, A., Pace, R., Zou, F., Zariwala, M., Fargo, D., Xu, A., Dunn, J. M., Darrah, R. J., and 9 others. Genetic modifiers of lung disease in cystic fibrosis. New Eng. J. Med. 353: 1443-1453, 2005. [PubMed: 16207846] [Full Text: https://doi.org/10.1056/NEJMoa051469]
Dubois, C. M., Laprise, M.-H., Blanchette, F., Gentry, L. E., Leduc, R. Processing of transforming growth factor beta-1 precursor by human furin convertase. J. Biol. Chem. 270: 10618-10624, 1995. [PubMed: 7737999] [Full Text: https://doi.org/10.1074/jbc.270.18.10618]
Fujii, D., Brissenden, J. E., Derynck, R., Francke, U. Transforming growth factor beta gene maps to human chromosome 19 long arm and to mouse chromosome 7. Somat. Cell Molec. Genet. 12: 281-288, 1986. [PubMed: 3459257] [Full Text: https://doi.org/10.1007/BF01570787]
Fujii, D. M., Brissenden, J. E., Derynck, R., Francke, U. Transforming growth factor beta gene (TGFB) maps to human chromosome 19. (Abstract) Cytogenet. Cell Genet. 40: 632, 1985.
Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido, T., Hagoplan, S., and 22 others. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373: 523-527, 1995. [PubMed: 7845465] [Full Text: https://doi.org/10.1038/373523a0]
Gao, Y., Qian, W.-P., Dark, K., Toraldo, G., Lin, A. S. P., Guldberg, R. E., Flavell, R. A., Weitzmann, M. N., Pacifici, R. Estrogen prevents bone loss through transforming growth factor beta signaling in T cells. Proc. Nat. Acad. Sci. 101: 16618-16623, 2004. [PubMed: 15531637] [Full Text: https://doi.org/10.1073/pnas.0404888101]
Gelb, B. D. Marfan's syndrome and related disorders--more tightly connected than we thought. (Editorial) New Eng. J. Med. 355: 841-844, 2006. [PubMed: 16929000] [Full Text: https://doi.org/10.1056/NEJMe068122]
Ghoreschi, K., Laurence, A., Yang, X.-P., Tato, C. M., McGeachy, M. J., Konkel, J. E., Ramos, H. L., Wei, L., Davidson, T. S., Bouladoux, N., Grainger, J. R., Chen, Q., and 9 others. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467: 967-971, 2010. [PubMed: 20962846] [Full Text: https://doi.org/10.1038/nature09447]
Grainger, D. J., Heathcote, K., Chiano, M., Snieder, H., Kemp, P. R., Metcalfe, J. C., Carter, N. D., Spector, T. D. Genetic control of the circulating concentration of transforming growth factor type beta-1. Hum. Molec. Genet. 8: 93-97, 1999. [PubMed: 9887336] [Full Text: https://doi.org/10.1093/hmg/8.1.93]
Gupta, A., Gartner, J. J., Sethupathy, P., Hatzigeorgiou, A. G., Fraser, N. W. Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript. Nature 442: 82-85, 2006. Note: Retraction: Nature 451: 600 only, 2008. [PubMed: 16738545] [Full Text: https://doi.org/10.1038/nature04836]
Habashi, J. P., Judge, D. P., Holm, T. M., Cohn, R. D., Loeys, B. L., Cooper, T. K., Myers, L., Klein, E. C., Liu, G., Calvi, C., Podowski, M., Neptune, E. R., Halushka, M. K., Bedja, D., Gabrielson, K., Rifkin, D. B., Carta, L., Ramirez, F., Huso, D. L., Dietz, H. C. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312: 117-121, 2006. [PubMed: 16601194] [Full Text: https://doi.org/10.1126/science.1124287]
Han, G., Lu, S.-L, Li, A. G., He, W., Corless, C. L., Kulesz-Martin, M., Wang, X.-J. Distinct mechanisms of TGF-beta-1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J. Clin. Invest. 115: 1714-1723, 2005. [PubMed: 15937546] [Full Text: https://doi.org/10.1172/JCI24399]
Heldin, C.-H., Miyazono, K., ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465-471, 1997. [PubMed: 9393997] [Full Text: https://doi.org/10.1038/37284]
Hu, B., Jin, C., Zeng, X., Resch, J. M., Jedrychowski, M. P., Yang, Z., Desai, B. N., Banks, A. S., Lowell, B. B., Mathis, D., Spiegelman, B. M. Gamma delta T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578: 610-614, 2020. [PubMed: 32076265] [Full Text: https://doi.org/10.1038/s41586-020-2028-z]
Ikuno, Y., Kazlauskas, A. TGF-beta-1-dependent contraction of fibroblasts is mediated by the PDGF-alpha receptor. Invest. Ophthal. Vis. Sci. 43: 41-46, 2002. [PubMed: 11773010]
Jang, C.-W., Chen, C.-H., Chen, C.-C., Chen, J., Su, Y.-H., Chen, R.-H. TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nature Cell Biol. 4: 51-58, 2001. Note: Erratum: Nature Cell Biol. 4: 328 only, 2002. [PubMed: 11740493] [Full Text: https://doi.org/10.1038/ncb731]
Janssens, K., Gershoni-Baruch, R., Guanabens, N., Migone, N., Ralston, S., Bonduelle, M., Lissens, W., Van Maldergem, L., Vanhoenacker, F., Verbruggen, L., Van Hul, W. Mutations in the gene encoding the latency-associated peptide of TGF-beta-1 cause Camurati-Engelmann disease. Nature Genet. 26: 273-275, 2000. [PubMed: 11062463] [Full Text: https://doi.org/10.1038/81563]
Janssens, K., ten Dijke, P., Ralston, S. H., Bergmann, C., Van Hul, W. Transforming growth factor-beta-1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J. Biol. Chem. 278: 7718-7724, 2003. [PubMed: 12493741] [Full Text: https://doi.org/10.1074/jbc.M208857200]
Jobling, A. I., Nguyen, M., Gentle, A., McBrien, N. A. Isoform-specific changes in scleral transforming growth factor-beta expression and the regulation of collagen synthesis during myopia progression. J. Biol. Chem. 279: 18121-18126, 2004. [PubMed: 14752095] [Full Text: https://doi.org/10.1074/jbc.M400381200]
Kaartinen, V., Warburton, D. Fibrillin controls TGF-beta activation. Nature Genet. 33: 331-332, 2003. [PubMed: 12610545] [Full Text: https://doi.org/10.1038/ng0303-331]
Kaminski, N., Allard, J. D., Pittet, J. F., Zuo, F., Griffiths, M. J., Morris, D., Huang, X., Sheppard, D., Heller, R. A. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc. Nat. Acad. Sci. 97: 1778-1783, 2000. [PubMed: 10677534] [Full Text: https://doi.org/10.1073/pnas.97.4.1778]
Kinoshita, A., Fukumaki, Y., Shirahama, S., Miyahara, A., Nishimura, G., Haga, N., Namba, A., Ueda, H., Hayashi, H., Ikegawa, S., Seidel, J., Kinoshita, A., Niikawa, N., Yoshiura, K. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. (Letter) Am. J. Med. Genet. 127A: 104-107, 2004. [PubMed: 15103729] [Full Text: https://doi.org/10.1002/ajmg.a.20671]
Kinoshita, A., Saito, T., Tomita, H., Makita, Y., Yoshida, K., Ghadami, M., Yamada, K., Kondo, S., Ikegawa, S., Nishimura, G., Fukushima, Y., Nakagomi, T., Saito, H., Sugimoto, T., Kamegaya, M., Hisa, K., Murray, J. C., Taniguchi, N., Niikawa, N., Yoshiura, K. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nature Genet. 26: 19-20, 2000. [PubMed: 10973241] [Full Text: https://doi.org/10.1038/79128]
Knowles, M. R. Personal Communication. Chapel Hill, N.C. 10/26/2005.
Kotlarz, D., Marquardt, B., Baroy, T., Lee, W. S., Konnikova, L., Hollizeck, S., Magg, T., Lehle, A. S., Walz, C., Borggraefe, I., Hauck, F., Bufler, P., and 12 others. Human TGF-beta-1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nature Genet. 50: 344-348, 2018. [PubMed: 29483653] [Full Text: https://doi.org/10.1038/s41588-018-0063-6]
Lang, F., Klingel, K., Wagner, C. A., Stegen, C., Warntges, S., Friedrich, B., Lanzendorfer, M., Melzig, J., Moschen, I., Steuer, S., Waldegger, S., Sauter, M., and 9 others. Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc. Nat. Acad. Sci. 97: 8157-8162, 2000. [PubMed: 10884438] [Full Text: https://doi.org/10.1073/pnas.97.14.8157]
Li, A. G., Wang, D., Feng, X.-H., Wang, X.-J. Latent TGF-beta-1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. 23: 1770-1781, 2004. [PubMed: 15057277] [Full Text: https://doi.org/10.1038/sj.emboj.7600183]
Li, B., Khanna, A., Sharma, V., Singh, T., Suthanthiran, M., August, P. TGF-beta-1 DNA polymorphisms, protein levels, and blood pressure. Hypertension 33: 271-275, 1999. [PubMed: 9931116] [Full Text: https://doi.org/10.1161/01.hyp.33.1.271]
Lienart, S., Merceron, R., Vanderaa, C., Lambert, F., Colau, D., Stockis, J., van der Woning, B., De Haard, H., Saunders, M., Coulie, P. G., Savvides, S. N., Lucas, S. Structural basis of latent TGF-beta-1 presentation and activation by GARP on human regulatory T cells. Science 362: 952-956, 2018. [PubMed: 30361387] [Full Text: https://doi.org/10.1126/science.aau2909]
Lin, H.-K., Bergmann, S., Pandolfi, P. P. Cytoplasmic PML function in TGF-beta signalling. Nature 431: 205-211, 2004. [PubMed: 15356634] [Full Text: https://doi.org/10.1038/nature02783]
Liu, Y., Teige, I., Birnir, B., Issazadeh-Nivakas, S. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nature Med. 12: 518-525, 2006. [PubMed: 16633347] [Full Text: https://doi.org/10.1038/nm1402]
Long, J.-R., Liu, P.-Y., Liu, Y.-J., Lu, Y., Xiong, D.-H., Elze, L., Recker, R. R., Deng, H.-W. APOE and TGF-beta-1 genes are associated with obesity phenotypes. J. Med. Genet. 40: 918-924, 2003. [PubMed: 14684691] [Full Text: https://doi.org/10.1136/jmg.40.12.918]
Luo, S., Kleemann, G. A., Ashraf, J. M., Shaw, W. M., Murphy, C. T. TGF-beta and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance. Cell 143: 299-312, 2010. [PubMed: 20946987] [Full Text: https://doi.org/10.1016/j.cell.2010.09.013]
Mangan, P. R., Harrington, L. E., O'Quinn, D. B., Helms, W. S., Bullard, D. C., Elson, C. O., Hatton, R. D., Wahl, S. M., Schoeb, T. R., Weaver, C. T. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441: 231-234, 2006. [PubMed: 16648837] [Full Text: https://doi.org/10.1038/nature04754]
Mao, J.-H., Saunier, E. F., de Koning, J. P., McKinnon, M. M., Nakajima Higgins, M., Nicklas, K., Yang, H.-T., Balmain, A., Akhurst, R. J. Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility. Proc. Nat. Acad. Sci. 103: 8125-8130, 2006. [PubMed: 16702541] [Full Text: https://doi.org/10.1073/pnas.0602581103]
Matt, P., Schoenhoff, F., Habashi, J., Holm, T., Van Erp, C., Loch, D., Carlson, O. D., Griswold, B. F., Fu, Q., De Backer, J., Loeys, B., Huso, D. L., McDonnell, N. B., Van Eyk, J. E., Dietz, H. C., GenTAC Consortium. Circulating transforming growth factor-(beta) in Marfan syndrome. Circulation 120: 526-532, 2009. [PubMed: 19635970] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.108.841981]
McGowan, N. W. A., MacPherson, H., Janssens, K., Van Hul, W., Frith, J. C., Fraser, W. D., Ralston, S. H., Helfrich, M. H. A mutation affecting the latency-associated peptide of TGFb1 in Camurati-Engelmann disease enhances osteoclast formation in vitro. J. Clin. Endocr. Metab. 88: 3321-3326, 2003. [PubMed: 12843182] [Full Text: https://doi.org/10.1210/jc.2002-020564]
Morris, D. G., Huang, X., Kaminski, N., Wang, Y., Shapiro, S. D., Dolganov, G., Glick, A., Sheppard, D. Loss of integrin alpha-v-beta-6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature 422: 169-173, 2003. [PubMed: 12634787] [Full Text: https://doi.org/10.1038/nature01413]
Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., Cheroutre, H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256-260, 2007. [PubMed: 17569825] [Full Text: https://doi.org/10.1126/science.1145697]
Munger, J. S., Huang, X., Kawakatsu, H., Griffiths, M. J., Dalton, S. L., Wu, J., Pittet, J. F., Kaminski, N., Garat, C., Matthay, M. A., Rifkin, D. B., Sheppard, D. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96: 319-328, 1999. [PubMed: 10025398] [Full Text: https://doi.org/10.1016/s0092-8674(00)80545-0]
Naka, K., Hoshii, T., Muraguchi, T., Tadokoro, Y., Ooshio, T., Kondo, Y., Nakao, S., Motoyama, N., Hirao, A. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463: 676-680, 2010. [PubMed: 20130650] [Full Text: https://doi.org/10.1038/nature08734]
Neptune, E. R., Frischmeyer, P. A., Arking, D. E., Myers, L., Bunton, T. E., Gayraud, B., Ramirez, F., Sakai, L. Y., Dietz, H. C. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nature Genet. 33: 407-411, 2003. [PubMed: 12598898] [Full Text: https://doi.org/10.1038/ng1116]
Ng, C. M., Cheng, A., Myers, L. A., Martinez-Murillo, F., Jie, C., Bedja, D., Gabrielson, K. L., Hausladen, J. M. W., Mecham, R. P., Judge, D. P., Dietz, H. C. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J. Clin. Invest. 114: 1586-1592, 2004. [PubMed: 15546004] [Full Text: https://doi.org/10.1172/JCI22715]
Phillips, J. A., III, Poling, J. S., Phillips, C. A., Stanton, K. C., Austin, E. D., Cogan, J. D., Wheeler, L., Yu, C., Newman, J. H., Dietz, H. C., Loyd, J. E. Synergistic heterozygosity for TGF-beta-1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genet. Med. 10: 359-365, 2008. [PubMed: 18496036] [Full Text: https://doi.org/10.1097/GIM.0b013e318172dcdf]
Pittet, J. F., Griffiths, M. J., Geiser, T., Kaminski, N., Dalton, S. L., Huang, X., Brown, L. A., Gotwals, P. J., Koteliansky, V. E., Matthay, M. A. Sheppard, D. TGF-beta is a critical mediator of acute lung injury. J. Clin. Invest. 107: 1537-1544, 2001. [PubMed: 11413161] [Full Text: https://doi.org/10.1172/JCI11963]
Prante, C., Milting, H., Kassner, A., Farr, M., Ambrosius, M., Schon, S., Seidler, D. G., El Banayosy, A., Korfer, R., Kuhn, J., Kleesiek, K., Gotting, C. Transforming growth factor beta-1-regulated xylosyltransferase I activity in human cardiac fibroblasts and its impact for myocardial remodeling. J. Biol. Chem. 282: 26441-26449, 2007. [PubMed: 17635914] [Full Text: https://doi.org/10.1074/jbc.M702299200]
Reeves, W. B., Andreoli, T. E. Transforming growth factor beta contributes to progressive diabetic nephropathy. Proc. Nat. Acad. Sci. 97: 7667-7669, 2000. [PubMed: 10884396] [Full Text: https://doi.org/10.1073/pnas.97.14.7667]
Roberts, A. B., Sporn, M. B., Assoian, R. K., Smith, J. M., Roche, N. S., Wakefield, L. M., Heine, U. I., Liotta, L. A., Falanga, V., Kehrl, J. H., Fauci, A. S. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Nat. Acad. Sci. 83: 4167-4171, 1986. [PubMed: 2424019] [Full Text: https://doi.org/10.1073/pnas.83.12.4167]
Saito, T., Kinoshita, A., Yoshiura, K., Makita, Y., Wakui, K., Honke, K., Niikawa, N., Taniguchi, N. Domain-specific mutations of a transforming growth factor (TGF)-beta 1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-beta 1. J. Biol. Chem. 276: 11469-11472, 2001. [PubMed: 11278244] [Full Text: https://doi.org/10.1074/jbc.C000859200]
Sancho, D., Gomez, M., Viedma, F., Esplugues, E., Gordon-Alonso, M., Garcia-Lopez, M. A., de la Fuente, H., Martinez-A, C., Lauzurica, P., Sanchez-Madrid, F. CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis. J. Clin. Invest. 112: 872-882, 2003. [PubMed: 12975472] [Full Text: https://doi.org/10.1172/JCI19112]
Scandura, J. M., Boccuni, P., Massague, J., Nimer, S. D. Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 upregulation. Proc. Nat. Acad. Sci. 101: 15231-15236, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 101: 16707 only, 2004. [PubMed: 15477587] [Full Text: https://doi.org/10.1073/pnas.0406771101]
Shah, R., Hurley, C. K., Posch, P. E. A molecular mechanism for the differential regulation of TGF-beta-1 expression due to the common SNP -509C-T (c.-1347C-T). Hum. Genet. 120: 461-469, 2006. [PubMed: 16896927] [Full Text: https://doi.org/10.1007/s00439-006-0194-1]
Shah, R., Rahaman, B., Hurley, C. K., Posch, P. E. Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum. Genet. 119: 61-74, 2006. [PubMed: 16369764] [Full Text: https://doi.org/10.1007/s00439-005-0112-y]
Sharma, K., Jin, Y., Guo, J., Ziyadeh, F. N. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45: 522-530, 1996. [PubMed: 8603776] [Full Text: https://doi.org/10.2337/diab.45.4.522]
Shehata, M., Schwarzmeier, J. D., Hilgarth, M., Hubmann, R., Duechler, M., Gisslinger, H. TGF-beta-1 induces bone marrow reticulin fibrosis in hairy cell leukemia. J. Clin. Invest. 113: 676-685, 2004. [PubMed: 14991065] [Full Text: https://doi.org/10.1172/JCI19540]
Shenkar, R., Coulson, W. F., Abraham, E. Hemorrhage and resuscitation induce alterations in cytokine expression and the development of acute lung injury. Am. J. Resp. Cell. Molec. Biol. 10: 290-297, 1994. [PubMed: 8117448] [Full Text: https://doi.org/10.1165/ajrcmb.10.3.8117448]
Shi, M., Zhu, J., Wang, R., Chen, X., Mi, L., Walz, T., Springer, T. A. Latent TGF-beta structure and activation. Nature 474: 343-349, 2011. [PubMed: 21677751] [Full Text: https://doi.org/10.1038/nature10152]
Siegel, P. M., Shu, W., Cardiff, R. D., Muller, W. J., Massague, J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Nat. Acad. Sci. 100: 8430-8435, 2003. [PubMed: 12808151] [Full Text: https://doi.org/10.1073/pnas.0932636100]
Sporn, M. B., Roberts, A. B., Wakefield, L. M., Assoian, R. K. Transforming growth factor-beta: biological function and chemical structure. Science 233: 532-534, 1986. [PubMed: 3487831] [Full Text: https://doi.org/10.1126/science.3487831]
Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q., Luo, K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286: 771-774, 1999. [PubMed: 10531062] [Full Text: https://doi.org/10.1126/science.286.5440.771]
Suthanthiran, M., Khanna, A., Cukran, D., Adhikarla, R., Sharma, V. K., Singh, T., August, P. Transforming growth factor-beta-1 hyperexpression in African American end-stage renal disease patients. Kidney Int. 53: 639-644, 1998. [PubMed: 9507209] [Full Text: https://doi.org/10.1046/j.1523-1755.1998.00858.x]
Suthanthiran, M., Li, B., Song, J. O., Ding, R., Sharma, V. K., Schwartz, J. E., August, P. Transforming growth factor-beta-1 hyperexpression in African-American hypertensives: a novel mediator of hypertension and/or target organ damage. Proc. Nat. Acad. Sci. 97: 3479-3484, 2000. [PubMed: 10725360] [Full Text: https://doi.org/10.1073/pnas.97.7.3479]
Tang, Y., McKinnon, M. L., Leong, L. M., Rusholme, S. A. B., Wang, S., Akhurst, R. J. Genetic modifiers interact with maternal determinants in vascular development of Tgfb1-/- mice. Hum. Molec. Genet. 12: 1579-1589, 2003. [PubMed: 12812985] [Full Text: https://doi.org/10.1093/hmg/ddg164]
Tang, Y., Wu, X., Lei, W., Pang, L., Wan, C., Shi, Z., Zhao, L., Nagy, N. R., Peng, X., Hu, J., Feng, X., Van Hul, W., Wan, M., Cao, X. TGF-beta-1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nature Med. 15: 757-765, 2009. [PubMed: 19584867] [Full Text: https://doi.org/10.1038/nm.1979]
Thyagarajan, T., Sreenath, T., Cho, A., Wright, J. T., Kulkarni, A. B. Reduced expression of dentin sialophosphoprotein is associated with dysplastic dentin in mice overexpressing transforming growth factor-beta-1 in teeth. J. Biol. Chem. 276: 11016-11020, 2001. [PubMed: 11116156] [Full Text: https://doi.org/10.1074/jbc.M010502200]
Tili, E., Michaille, J.-J., Liu, C.-G., Alder, H., Taccioli, C., Volinia, S., Calin, G. A., Croce, C. M. GAM/ZFp/ZNF512B is central to a gene sensor circuitry involving cell-cycle regulators, TGF-beta effectors, Drosha and microRNAs with opposite oncogenic potentials. Nucleic Acids Res. 38: 7673-7688, 2010. [PubMed: 20639536] [Full Text: https://doi.org/10.1093/nar/gkq637]
Valderrama-Carvajal, H., Cocolakis, E., Lacerte, A., Lee, E.-H., Krystal, G., Ali, S., Lebrun, J.-J. Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nature Cell Biol. 4: 963-969, 2002. [PubMed: 12447389] [Full Text: https://doi.org/10.1038/ncb885]
Veldhoen, M., Uyttenhove, C., van Snick, J., Helmby, H., Westendorf, A., Buer, J., Martin, B., Wilhelm, C., Stockinger, B. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immun. 9: 1341-1346, 2008. [PubMed: 18931678] [Full Text: https://doi.org/10.1038/ni.1659]
Waldegger, S., Klingel, K., Barth, P., Sauter, M., Lanzendorfer, M., Kandolf, R., Lang, F. h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116: 1081-1088, 1999. [PubMed: 10220500] [Full Text: https://doi.org/10.1016/s0016-5085(99)70011-9]
Wandzioch, E., Zaret, K. S. Dynamic signaling network for the specification of embryonic pancreas and liver progenitors. Science 324: 1707-1710, 2009. [PubMed: 19556507] [Full Text: https://doi.org/10.1126/science.1174497]
Watanabe, Y., Kinoshita, A., Yamada, T., Ohta, T., Kishino, T., Matsumoto, N., Ishikawa, M., Niikawa, N., Yoshiura, K.-I. A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-beta-1 (TGF-beta-1) and its signaling pathway. J. Hum. Genet. 47: 478-483, 2002. [PubMed: 12202987] [Full Text: https://doi.org/10.1007/s100380200069]
Wurdak, H., Ittner, L. M., Lang, K. S., Leveen, P., Suter, U., Fischer, J. A., Karlsson, S., Born, W., Sommer, L. Inactivation of TGF-beta signaling in neural crest stem cells leads to multiple defects reminiscent of DiGeorge syndrome. Genes Dev. 19: 530-535, 2005. [PubMed: 15741317] [Full Text: https://doi.org/10.1101/gad.317405]
Wyss-Coray, T., Lin, C., Yan, F., Yu, G., Rohde, M., McConlogue, L., Masliah, E., Mucke, L. TGF-beta-1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nature Med. 7: 612-618, 2001. [PubMed: 11329064] [Full Text: https://doi.org/10.1038/87945]
Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., Mucke, L. Amyloidogenic role of cytokine TGF-beta-1 in transgenic mice and in Alzheimer's disease. Nature 389: 603-606, 1997. [PubMed: 9335500] [Full Text: https://doi.org/10.1038/39321]
Yang, L., Anderson, D. E., Baecher-Allan, C., Hastings, W. D., Bettelli, E., Oukka, M., Kuchroo, V. K., Hafler, D. A. IL-21 and TGF-beta are required for differentiation of human TH17 cells. Nature 454: 350-352, 2008. [PubMed: 18469800] [Full Text: https://doi.org/10.1038/nature07021]
Yang, Z., Mu, Z., Dabovic, B., Jurukovski, V., Yu, D., Sung, J., Xiong, X., Munger, J. S. Absence of integrin-mediated TGF-beta-1 activation in vivo recapitulates the phenotype of TGF-beta-1 null mice. J. Cell Biol. 176: 787-793, 2007. [PubMed: 17353357] [Full Text: https://doi.org/10.1083/jcb.200611044]
Zeisberg, E. M., Tarnavski, O., Zeisberg, M., Dorfman, A. L., McMullen, J. R., Gustafsson, E., Chandraker, A., Yuan, X., Pu, W. T., Roberts, A. B., Neilson, E. G., Sayegh, M. H., Izumo, S., Kalluri, R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Med. 13: 952-961, 2007. [PubMed: 17660828] [Full Text: https://doi.org/10.1038/nm1613]
Zhang, L., Chen, S. X., Guerrero-Juarez, C. F., Li, F., Tong, Y., Liang, Y., Liggins, M., Chen, X., Chen, H., Li, M., Hata, T., Zheng, Y., Plikus, M. V., Gallo, R. L. Age-related loss of innate immune antimicrobial function of dermal fat is mediated by transforming growth factor beta. Immunity 50: 121-136, 2019. [PubMed: 30594464] [Full Text: https://doi.org/10.1016/j.immuni.2018.11.003]
Ziyadeh, F. N., Hoffman, B. B., Han, D. C., Iglesias-de la Cruz, M. C., Hong, S. W., Isono, M., Chen, S., McGowan, T. A., Sharma, K. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc. Nat. Acad. Sci. 97: 8015-8020, 2000. [PubMed: 10859350] [Full Text: https://doi.org/10.1073/pnas.120055097]