HGNC Approved Gene Symbol: RREB1
Cytogenetic location: 6p24.3 Genomic coordinates (GRCh38): 6:7,107,743-7,251,980 (from NCBI)
In several neuroendocrine cell types, the RAS/RAF signal transduction cascade results in cell differentiation (see HRAS; 190020). This signal transduction cascade involves inactivation of several tiers of protein kinases, including members of the RAF (e.g., RAF1, 164760), MAPKK, and MAPK families (see 176872). Ultimately, activation of these protein kinases results in the activation of transcription factors responsible for changes in cell phenotype. In the human medullary thyroid carcinoma cell line TT, an activated HRAS oncogene or activation of the RAF1 gene induces a program of neuroendocrine differentiation (Carson et al., 1995). One of the hallmarks of this differentiation process is an increase in the expression of the calcitonin gene (114130). Thiagalingam et al. (1996) reported the DNA affinity cloning of a RAS-responsive element binding protein, RREB1, from the TT cell line. RREB1, a zinc finger transcription factor, was shown to bind specifically to the distal RAS-responsive element (RRE) in the calcitonin gene promoter and to augment the RAS/RAF-mediated transcriptional response of that promoter. Thus, they concluded that it may be involved in RAS/RAF-mediated cell differentiation.
Using a promoter pull-down assay followed by mass spectrometry analysis, Flajollet et al. (2009) identified RREB1 as a protein that bound the HLA-G (142871) promoter. RREB1 exerted repressive activity on the promoter in HLA-G-negative cells that was mediated by recruitment of HDAC1 (601241) and CTBP1 (602618) and/or CTBP2 (602619). CTBP1 and CTBP2 are subunits of the C-terminal binding protein (CTBP) complex, a corepressor involved in chromatin remodeling. The HLA-G promoter contains 3 RREB1 target sites. Flajollet et al. (2009) proposed that the repressive activity of RREB1 on the HLA-G promoter may be regulated by posttranslational modifications governing its association with CTBP.
Su et al. (2020) identified RREB1, a RAS (see 190070) transcriptional effector, as a key partner of TGF-beta (190180)-activated SMAD (see 600993) transcription factors in epithelial-to-mesenchymal transitions (EMTs). MAPK-activated RREB1 recruits TGF-beta-activated SMAD factors to SNAIL (see 604238). Context-dependent chromatin accessibility dictated the ability of RREB1 and SMAD to activate additional genes that determined the nature of the resulting EMT. In carcinoma cells, TGF-beta-SMAD and RREB1 directly drove expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumor growth. In mouse epiblast progenitors, Nodal (601265)-SMAD and RREB1 combined to induce expression of SNAIL and mesendoderm differentiation genes that drove gastrulation. Thus, Su et al. (2020) concluded that RREB1 provides a molecular link between RAS and TGF-beta pathways for coordinated induction of developmental and fibrogenic EMTs.
Kent et al. (2020) examined the role of RREB1 in the RAS-MAPK pathway in HEK293 cells. ChIP-seq experiments showed that RREB1 targeted gene pathways enriched for MAPK signaling, and RREB1 knockdown studies followed by RNA-seq confirmed enrichment for interaction with MAPK target genes, including HRAS, MAP2K2 (601263), AKT1 (164730), DUSP7 (602749), and FGFR4 (134935). Kent et al. (2020) further showed that RREB1 recruited SIN3A (607776) and KDM1A (609132) to target proteins and regulate histone modification, leading to transcriptional inactivation of MAPK signaling components. Heterozygous loss of RREB1 resulted in loss of lysine demethylase activity at RREB1 target promoters and enhanced transcription resulting in MAPK pathway activation.
Thiagalingam et al. (1997) mapped the RREB1 gene to chromosome 6p25 by 3 mapping methods: PCR analysis of a somatic cell hybrid panel, analysis of the Stanford G3 radiation hybrid mapping panel, and fluorescence in situ hybridization.
Kent et al. (2020) reported a new patient and reviewed 7 published patients and 7 patients reported in the ClinVar database with chromosome 6p interstitial microdeletions encompassing chromosome 6p25.1-p24.3 (612582). The patients had clinical features consistent with a Noonan (see 163950)-spectrum disorder, including short stature, dysmorphic facial features, and cardiovascular abnormalities. Kent et al. (2020) found that the RREB1 gene was in the common deleted region in these patients. RREB gene expression was decreased in lymphoblastoid cells (LCLs) from the newly reported patient. The patient-derived LCLs also had increased phosphorylated MEK (see 176872) and ERK (see 601795) when stimulated with FBS and had increased proliferation compared to control cells, consistent with abnormal RAS-MAPK pathway activity.
Kent et al. (2020) used CRISPR/Cas9 gene editing to generate a Rreb1 knockout mouse. Heterozygous knockout mice were smaller and had significantly increased intercanthal distance and a wider blunted nose compared to wildtype littermates. The heterozygous knockout mice developed left ventricular hypertrophy and reduced fractional shortening at 6 months of age. Murine embryonic fibroblasts derived from Rreb1 heterozygous knockout embryos had increased Mapk activity and proliferation following stimulation with FBS compared to wildtype.
Carson, E. B., McMahon, M., Baylin, S. B., Nelkin, B. D. Ret gene silencing is associated with Raf-1-induced medullary thyroid carcinoma cell differentiation. Cancer Res. 55: 2048-2052, 1995. [PubMed: 7743500]
Flajollet, S., Poras, I., Carosella, E. D., Moreau, P. RREB-1 is a transcriptional repressor of HLA-G. J. Immun. 183: 6948-6959, 2009. [PubMed: 19890057] [Full Text: https://doi.org/10.4049/jimmunol.0902053]
Kent, O. A., Saha, M., Coyaud, E., Burston, H. E., Law, N., Dadson, K., Chen, S., Laurent, E. M., St-Germain, J., Sun, R. X., Matsumoto, Y., Cowen, J., and 10 others. Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes. Nature Commun. 11: 4673, 2020. [PubMed: 32938917] [Full Text: https://doi.org/10.1038/s41467-020-18483-9]
Su, J., Morgani, S. M., David, C. J., Wang, Q., Er, E. E., Huang, Y.-H., Basnet, H., Zou, Y., Shu, W., Soni, R. K., Hendrickson, R. C., Hadjantonakis, A.-K., Massague, J. TGF-beta orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1. Nature 577: 566-571, 2020. Note: Erratum: Nature 578: E11, 2020. [PubMed: 31915377] [Full Text: https://doi.org/10.1038/s41586-019-1897-5]
Thiagalingam, A., De Bustros, A., Borges, M., Jasti, R., Compton, D., Diamond, L., Mabry, M., Ball, D. W., Baylin, S. B., Nelkin, B. D. RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas. Molec. Cell. Biol. 16: 5335-5345, 1996. [PubMed: 8816445] [Full Text: https://doi.org/10.1128/MCB.16.10.5335]
Thiagalingam, A., Lengauer, C., Baylin, S. B., Nelkin, B. D. RREB1, a Ras responsive element binding protein, maps to human chromosome 6p25. Genomics 45: 630-632, 1997. [PubMed: 9367691] [Full Text: https://doi.org/10.1006/geno.1997.5001]