RREB1 and Associated Diseases
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Backgrounds of RREB1
RREB1 is a large gene spanning 144 kB with at least 12 isoforms. It encodes a zinc finger transcription factor that is expressed in several T2D-relevant tissues, including pancreatic islets, adipose tissue, liver, and skeletal muscle. RREB1 is considered a potential human oncogene and is overexpressed in thyroid cancer by conferring increased transactivation of the calcitonin gene in response to Ras signal transduction. It is also in the development of gastric cancer and is associated with cell proliferation. RREB1 is a zinc finger transcription factor that acts downstream of RAS. It is evolutionarily conserved, widely expressed, can function both as a transcriptional repressor and activator, and interacts with several signaling pathways, including EGFR/MAPK, and JNK/MAPK, which regulate RREB1 through phosphorylation, and JAK/STAT, TGF-b/SMAD, Notch, and Sonic Hedgehog, which cooperate with RREB1 in transcriptional regulation. RREB1 is also a candidate for the onset of DiGeorge syndrome, which is associated with craniofacial deformities including cleft palate.
Functions of RREB1
RREB1 is an oncogene in many types of cancer and is involved in a variety of biological processes such as DNA damage repair, cell growth and proliferation, cell differentiation, fat development, and fasting glucose balance. In humans, RREB1 acts as a transcriptional repressor of HLA-G, a secreted factor that regulates vascular remodeling and immune evasion of tumor cells. The transcription factor RREB1 is necessary for invertebrate development and is implicated in cancer, suggesting that it plays critical contextual organismal functions. RREB1 plays a key role in epithelial-mesenchymal transitions (EMTs) during embryonic gastronomic development by integrating TGF-β and Ras signals. RREB1 has been shown to form heteromeric complexes with DJ1 for gene regulation of the neuropeptide CCK1, and DJ1 is known to have additional roles in PD etiology outside of the nucleus.
Fig.1 RREB1 regulates different target genes in different cancers. (Deng, 2020)
Different Expression of RREB1 in Diseases
Mutation or altered expression of RREB1 has been linked to leukemia, melanoma, thyroid, and prostate cancers, as well as pancreatic and colorectal cancer metastasis. In adult mice, loss of the RREB1 single allele results in Noonan-like RASopathies, including craniofacial and cardiovascular defects. RREB1 is highly expressed in gastric cancer, and the down-regulation of RREB1 can inhibit cell proliferation by enhancing the expression of p16.
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Reference
- Deng, Y.N.; et al. Transcription factor RREB1: from target genes towards biological functions. International Journal of Biological Sciences. 2020, 16(8): 1463.
