Alternative titles; symbols
HGNC Approved Gene Symbol: THBS1
Cytogenetic location: 15q14 Genomic coordinates (GRCh38): 15:39,581,079-39,599,466 (from NCBI)
Thrombospondin I is a multimodular secreted protein that associates with the extracellular matrix and possesses a variety of biologic functions, including a potent antiangiogenic activity. Other thrombospondin genes include thrombospondins II (THBS2; 188061), III (THBS3; 188062), and IV (THBS4; 600715).
Thrombospondin (THBS) is a homotrimeric glycoprotein with disulfide-linked subunits of 180 kD. THBS was first described as a component of the alpha-granule of platelets, released on platelet activation. It is associated with the platelet membrane in the presence of divalent cations and has a role in platelet aggregation. THBS is not limited to platelets, however. It is synthesized and secreted for incorporation into the extracellular matrix by a variety of cells including endothelial cells, fibroblasts, smooth muscle cells, and type II pneumocytes. THBS binds heparin, sulfatides, fibrinogen, fibronectin, plasminogen, and type V collagen. Dixit et al. (1986) reported characterization of a cDNA encoding the N-terminal 376 amino acid residues of human THBS. Asch et al. (1987) identified an 88-kD glycoprotein which they concluded functions as the cellular THBS receptor. Frazier (1987) reviewed the molecular structure of thrombospondin.
Using real-time RT-PCR, Hirose et al. (2008) detected specific and high expression levels of both THBS1 and THBS2 in human intervertebral disc tissue.
De Fraipont et al. (2000) measured the cytosolic concentrations of 3 proteins involved in angiogenesis, namely, platelet-derived endothelial cell growth factor (PDECGF; 131222), VEGFA (192240), and THBS1 in a series of 43 human sporadic adrenocortical tumors. The tumors were classified as adenomas, transitional tumors, or carcinomas. PDECGF/thymidine phosphorylase levels were not significantly different among these 3 groups. One hundred percent of the adenomas and 73% of the transitional tumors showed VEGFA concentrations under the threshold value of 107 ng/g protein, whereas 75% of the carcinomas had VEGFA concentrations above this threshold value. Similarly, 89% of the adenomas showed THBS1 concentrations above the threshold value of 57 microg/g protein, whereas only 25% of the carcinomas and 33% of the transitional tumor samples did so. IGF2 (147470) overexpression, a common genetic alteration of adrenocortical carcinomas, was significantly correlated with higher VEGFA and lower THBS1 concentrations. The authors concluded that a decrease in THBS1 expression is an event that precedes an increase in VEGFA expression during adrenocortical tumor progression. The population of premalignant tumors with low THBS1 and normal VEGFA levels could represent a selective target for antiangiogenic therapies.
Natural inhibitors of angiogenesis are able to block pathologic neovascularization without harming the preexisting vasculature. Volpert et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I and pigment epithelium-derived factor (172860), derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (134637; 134638)-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The antiangiogenic activity of thrombospondin I and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. Volpert et al. (2002) concluded that this example of cooperation between pro- and antiangiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction.
Volpert et al. (2002) found that Id1 (600349) is a potent inhibitor of Tsp1 transcription in mouse embryonic fibroblasts. In Id1 null mice, upregulated expression of Tsp1 led to suppression of angiogenesis.
Chemotherapeutic drugs chronically administered to tumor-bearing mice using a frequent schedule at doses substantially lower than the maximum tolerated dose (i.e., metronomic dosing) can cause sustained and potent antiangiogenic effects by targeting endothelial cells of newly growing tumor blood vessels. Bocci et al. (2003) found that protracted exposure of endothelial cells in vitro to low concentrations of several different anticancer agents caused marked induction of Tsp1. Increases in circulating Tsp1 were also detected in the plasma of human tumor-bearing severe combined immunodeficient mice treated with metronomic low-dose cyclophosphamide. The antiangiogenic and antitumor effects of low-dose continuous cyclophosphamide were lost in Tsp1-null mice, whereas these effects were retained by using a maximum tolerated dose of the same drug. Bocci et al. (2003) concluded that TSP1 is a secondary mediator of the antiangiogenic effects of at least some low-dose metronomic chemotherapy regimens.
Christopherson et al. (2005) found that immature but not mature astrocytes expressed TSP1 and TSP2, and these TSPs promoted central nervous system (CNS) synaptogenesis in vitro and in vivo. TSPs induced ultrastructurally normal synapses that were presynaptically active but postsynaptically silent and worked in concert with other, as yet unidentified, astrocyte-derived signals to produce functional synapses. These studies identified TSPs as CNS synaptogenic proteins, provided evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggested that TSP1 and TSP2 act as a permissive switch that times CNS synaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.
Isenberg et al. (2005) found that endogenous Tsp1 limited the angiogenic response to nitric oxide (NO) in mouse muscle explant assays. In human umbilical vein endothelial cells, TSP1 was a potent antagonist of NO-induced chemotaxis, adhesion, and proliferation. TSP1 antagonized these cGMP-dependent endothelial responses to NO both upstream and downstream of cGMP signaling.
Ridnour et al. (2005) found that slow and prolonged release of NO at various concentrations produced a triphasic response in TSP1 protein expression in human umbilical vein endothelial cells. Expression of TSP1 decreased at 0.1 micromolar NO, rebounded at 100 micromolar NO, and decreased again at 1,000 micromolar NO. These same conditions produced a dose-dependent increase in TP53 (191170) phosphorylation and inverse biphasic responses of ERK (see ERK1, or MAPK3; 601795) and MAP kinase phosphatase-1 (DUSP1; 600714). The growth-stimulating activity of low-dose NO and the suppression of TSP1 expression were both ERK dependent. Ridnour et al. (2005) concluded that dose-dependent positive and negative feedback loops exist between NO and TSP1.
Using cDNA microarrays, Thakar et al. (2005) found that Tsp1 was the transcript showing highest induction at 3 hours following ischemia/reperfusion (IR) injury in rat and mouse kidneys. Northern blot analysis demonstrated that Tsp1 expression was undetectable at baseline, induced at 3 and 12 hours, and returned to baseline at 48 hours of reperfusion. Immunocytochemical staining showed injured proximal tubules were the predominant site of expression of Tsp1 in IR injury and that Tsp1 colocalized with activated caspase-3 (600636). Addition of purified Tsp1 to normal rat kidney proximal tubule cells or to cells subjected to ATP depletion in vitro induced injury, and knockout of Tsp1 in mice afforded significant protection against IR injury-induced renal failure and tubular damage. Thakar et al. (2005) concluded that TSP1 is a regulator of ischemic damage in the kidney and plays a role in the pathophysiology of ischemic renal failure.
Taxanes, such as taxol and docetaxel, are a family of chemotherapeutic agents that have antineoplastic effects against a wide range of cancers. Lih et al. (2006) showed that upregulation of TXR1 (PRR13; 610459) impeded taxane-induced apoptosis in tumor cells by transcriptionally downregulating production of TSP1. Decreased TXR1 levels or treatment with TSP1 or a TSP1 mimetic peptide sensitized cells to taxane cytotoxicity by activating signaling through CD47 (601028), whereas interference with CD47 function reduced taxane-induced cell death. Cellular abundance of TXR1 and TSP1 varied inversely, and taxol cytotoxicity showed a negative correlation with TXR1 expression and a positive correlation with TSP1 expression in 13 of 19 cancer cell lines examined. Lih et al. (2006) concluded that TXR1 is a regulator of TSP1 production.
Staniszewska et al. (2007) identified human THBS1 as a ligand for alpha-9 (ITGA9; 603963)/beta-1 (ITGB1; 135630) integrin, and they identified an integrin-binding site within the N-terminal domain (NTD) of THBS1. Binding of the NTD to human dermal microvascular endothelial cells expressing alpha-9/beta-1 integrin activated signaling proteins such as ERK1/ERK2 (MAPK1; 176948) and paxillin (PXN; 602505). Blocking alpha-9/beta-1 integrin by monoclonal antibody or snake venom disintegrin inhibited cell proliferation and NTD-induced cell migration. The THBS1 NTD also induced neovascularization in animal model systems, and this proangiogenic activity was inhibited by alpha-9/beta-1 inhibitors.
Wolf et al. (1990) showed that the type I repeating subunits of thrombospondin are encoded by symmetrical exons and that the heparin-binding domain is encoded by a single exon. The THBS1 message is encoded by 21 exons.
By in situ hybridization, Jaffe et al. (1990) mapped the THBS1 gene to human 15q15 and the cognate gene to mouse chromosome 2 (region F). Wolf et al. (1990) localized the THBS1 gene to 15q11-qter by Southern analysis of human-rodent somatic cell hybrids.
To explore the function of thrombospondin I in vivo, Lawler et al. (1998) disrupted the Thbs1 gene by homologous recombination in the mouse genome. Platelets from these mice were completely deficient in Thbs1 protein; however, thrombin-induced platelet aggregation was not diminished. The deficient mice displayed a mild and variable lordotic curvature of the spine that was apparent from birth. They also displayed an increase in the number of circulating white blood cells, with monocytes and eosinophils having the largest percent increases. Although other major organs showed no abnormalities consistent with high levels of expression of Thbs1 in lung, Lawler et al. (1998) observed abnormalities in the lungs of the mice lacking Thbs1. Extensive acute and organizing pneumonia with neutrophils and macrophages developed by 4 weeks of age. The macrophages stained for hemosiderin, indicating that diffuse alveolar hemorrhage was occurring. Later, the number of neutrophils decreased and a striking increase in the number of hemosiderin-containing macrophages was observed associated with multiple-lineage epithelial hyperplasia and the deposition of collagen and elastin. The results indicated that THBS1 is involved in normal lung homeostasis.
To ascertain the participation of the endogenous angiogenic inhibitor thrombospondin I in tumor progression, Rodriguez-Manzaneque et al. (2001) generated mammary tumor-prone mice that either lacked, or specifically overexpressed, Thbs1 in the mammary gland. Tumor burden and vasculature were significantly increased in Thbs1-deficient animals, and capillaries within the tumor appeared distended and sinusoidal. In contrast, Thbs1 overexpressors showed delayed tumor growth or lacked frank tumor development. Absence of Thbs1 resulted in increased association of vascular endothelial growth factor (VEGF; 192240) with its receptor VEGFR2 (191306) and higher levels of active matrix metalloproteinase-9 (MMP9; 120361), a molecule previously shown to facilitate both angiogenesis and tumor invasion. In vitro, enzymatic activation of pro-MMP9 was suppressed by Thbs1. Together these results argued for a protective role of endogenous inhibitors of angiogenesis in tumor growth and implicated Thbs1 in the in vivo regulation of metalloproteinase-9 activation and VEGF signaling.
Tran and Neary (2006) found that extracellular ATP, through the activation of P2RY4 receptors (300038), stimulated Tsp1 expression and release in rat cortical astrocytes and that this nucleotide-induced increase was mediated by protein kinase signaling pathways. They also found that Tsp1 expression was increased after mechanical strain using an in vitro model of CNS trauma and that the increase was again dependent on P2 receptors and protein kinase signaling.
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Lawler, J., Sunday, M., Thibert, V., Duquette, M., George, E. L., Rayburn, H., Hynes, R. O. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J. Clin. Invest. 101: 982-992, 1998. [PubMed: 9486968] [Full Text: https://doi.org/10.1172/JCI1684]
Lih, C.-J., Wei, W., Cohen, S. N. Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes. Genes Dev. 20: 2082-2095, 2006. [PubMed: 16847352] [Full Text: https://doi.org/10.1101/gad.1441306]
Ridnour, L. A., Isenberg, J. S., Espey, M. G., Thomas, D. D., Roberts, D. D., Wink, D. A. Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1. Proc. Nat. Acad. Sci. 102: 13147-13152, 2005. [PubMed: 16141331] [Full Text: https://doi.org/10.1073/pnas.0502979102]
Rodriguez-Manzaneque, J. C., Lane, T. F., Ortega, M. A., Hynes, R. O., Lawler, J., Iruela-Arispe, M. L. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc. Nat. Acad. Sci. 98: 12485-12490, 2001. [PubMed: 11606713] [Full Text: https://doi.org/10.1073/pnas.171460498]
Staniszewska, I., Zaveri, S., Del Valle, L., Oliva, I., Rothman, V. L., Croul, S. E., Roberts, D. D., Mosher, D. F., Tuszynski, G. P., Marcinkiewicz, C. Interaction of alpha-9/beta-1 integrin with thrombospondin-1 promotes angiogenesis. Circ. Res. 100: 1308-1316, 2007. [PubMed: 17413041] [Full Text: https://doi.org/10.1161/01.RES.0000266662.98355.66]
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Tran, M. D., Neary, J. T. Purinergic signaling induces thrombospondin-1 expression in astrocytes. Proc. Nat. Acad. Sci. 103: 9321-9326, 2006. [PubMed: 16754856] [Full Text: https://doi.org/10.1073/pnas.0603146103]
Volpert, O. V., Pili, R., Sikder, H. A., Nelius, T., Zaichuk, T., Morris, C., Shiflett, C. B., Devlin, M. K., Conant, K., Alani, R. M. Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1. Cancer Cell 2: 473-483, 2002. [PubMed: 12498716] [Full Text: https://doi.org/10.1016/s1535-6108(02)00209-x]
Volpert, O. V., Zaichuk, T., Zhou, W., Reiher, F., Ferguson, T. A., Stuart, P. M., Amin, M., Bouck, N. P. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nature Med. 8: 349-357, 2002. [PubMed: 11927940] [Full Text: https://doi.org/10.1038/nm0402-349]
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