|MEN1 menin 1. Homo sapiens (human) Gene ID: 4221|
|Human menin (MEN1) mRNA, complete cds GenBank: U93236.1|
|Crystal Structure of Human Menin. 3U84|
Menin is a 610-amino acid nuclear protein that in humans is encoded by the MEN1 (multiple endocrine neoplasia type 1) gene, located on long arm of chromosome 11 (11q13). Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited endocrine disease (famous as Wermer disease) in which more than one endocrine gland develops tumors or grows excessively without forming tumors as a consequence of the MEN1 gene mutation. Menin represses MEN1 through inhibiting cell proliferation through multiple mechanisms. 1) Menin interacts with various histonemodifying enzymes, such as MLL, EZH2 and HDACs, to affect gene transcription, leading to repression of cell proliferation. 2) Menin also interacts with various transcription factors, such as JunD, NF-κB, PPARγ and VDR, to induce or suppress gene transcription. As these various transcription factors are known to regulate cell proliferation, their interaction with menin may be relevant to menin's role in inhibiting cell proliferation. 3) Menin inhibits cell proliferation via TGF-β signaling and Wnt/β-catenin signaling pathways. 4) Menin represses certain pro-proliferative factors involved in endocrine tumors such as IGFBP-2, IGF2 and PTHrP to repress cell proliferation. 5) Menin affects cell cycle progression to inhibit cell proliferation.
MEN1 is an essential antifibrotic factor in renal fibrogenesis and could be a potential target for antifibrotic therapy. Since knockout of MEN1 resulted in chronic renal fibrosis and unilateral ureteral obstruction (UUO)-induced tubulointerstitial fibrosis (TIF), which is associated with an increased induction of epithelial-to-mesenchymal transition (EMT), G2/M arrest and JNK signaling. Mechanistically, menin recruits and increases H3K4me3 at the promoter regions of hepatocyte growth factor (HGF) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (Adamts5) genes and enhances their transcriptional activation. The levels of menin by degrees diminish with the progression of fibrosis in a mouse model of radiation‐induced pulmonary fibrosis. MEN1 plays a key role in the formation of pulmonary fibrosis by regulating the secretion of TGF-β and the activation of TGF-β/Smads signaling pathway.
The expression of menin is reduced in the liver of aging mice. Hepatocyte-specific deletion of Men1 induces liver steatosis in aging mice. Menin deficiency promotes high-fat diet-induced liver steatosis in mice. Menin recruits SIRT1 to control hepatic CD36 expression and triglyceride accumulation through histone.
Menin plays important roles in neuroinflammation and brain development.
The hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.
- Guru, S. C., Goldsmith, P. K., Burns, A. L., Marx, S. J., Spiegel, A. M., Collins, F. S., & Chandrasekharappa, S. C. (1998). Menin, the product of the MEN1 gene, is a nuclear protein. Proceedings of the National Academy of Sciences, 95(4), 1630-1634. PMID: 9465067 PMCID: PMC19125 DOI: 10.1073/pnas.95.4.1630
- Larsson, C., Skogseid, B., Öberg, K., Nakamura, Y., & Nordenskjöld, M. (1988). Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature, 332(6159), 85-87. PMID: 2894610 DOI: 10.1038/332085a0
- Bale, A. E., Norton, J. A., Wong, E. L., Fryburg, J. S., Maton, P. N., Oldfield, E. H., ... & Marx, S. J. (1991). Allelic Loss on Chromosome 11 in Hereditary and Sporadic Tumors Related to Familial Multiple Endocrine Neoplasia Type. Cancer research, 51(4), 1154-1157. PMID: 1671755
- Wu, T., & Hua, X. (2011). Menin represses tumorigenesis via repressing cell proliferation. American journal of cancer research, 1(6), 726. PMID: 22016823 PMCID: PMC3195934
- Ren, F., Guo, Q., & Zhou, H. (2023). Menin represses the proliferation of gastric cancer cells by interacting with IQGAP1. Biomedical Reports, 18(4), 1-7.
- Jin, B., Zhu, J., Zhou, Y., Liang, L., Yang, Y., Xu, L., ... & Li, H. (2022). Loss of MEN1 leads to renal fibrosis and decreases HGF‐Adamts5 pathway activity via an epigenetic mechanism. Clinical and Translational Medicine, 12(8), e982. PMID: 35968938 PMCID: PMC9377152 DOI: 10.1002/ctm2.982
- Wei, W., Zhang, H. Y., Gong, X. K., Dong, Z., Chen, Z. Y., Wang, R., ... & Jin, S. Z. (2018). Mechanism of MEN1 gene in radiation-induced pulmonary fibrosis in mice. Gene, 678, 252-260. PMID: 30099020 DOI: 10.1016/j.gene.2018.08.039
- Cao, Y., Xue, Y., Xue, L., Jiang, X., Wang, X., Zhang, Z., ... & Ning, G. (2013). Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation. Journal of Hepatology, 59(6), 1299-1306. PMID: 23867312 DOI: 10.1016/j.jhep.2013.07.011
- Matkar, S., Thiel, A., & Hua, X. (2013). Menin: a scaffold protein that controls gene expression and cell signaling. Trends in biochemical sciences, 38(8), 394-402. PMID: 23850066 PMCID: PMC3741089 DOI: 10.1016/j.tibs.2013.05.005
- Feng, Z., Ma, J., & Hua, X. (2017). Epigenetic regulation by the menin pathway. Endocrine-related cancer, 24(10), T147. PMID: 28811300 PMCID: PMC5612327 DOI: 10.1530/ERC-17-0298
- Leng, L., Yuan, Z., Su, X., Chen, Z., Yang, S., Chen, M., ... & Zhang, J. (2023). Hypothalamic Menin regulates systemic aging and cognitive decline. Plos Biology, 21(3), e3002033. PMID: 36928253 PMCID: PMC10019680 DOI: 10.1371/journal.pbio.3002033
- Yang, Y. J., Song, T. Y., Park, J., Lee, J., Lim, J., Jang, H., ... & Cho, E. J. (2013). Menin mediates epigenetic regulation via histone H3 lysine 9 methylation. Cell death & disease, 4(4), e583-e583. PMID: 23579270 PMCID: PMC3668625 DOI: 10.1038/cddis.2013.98
- Lin, J., Wu, Y., Tian, G., Yu, D., Yang, E., Lam, W. H., ... & Li, X. D. (2023). Menin “reads” H3K79me2 mark in a nucleosomal context. Science, 379(6633), 717-723. PMID: 36795828 DOI: 10.1126/science.adc9318
- Agarwal, S. K. (2017). The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocrine-related cancer, 24(10), T119. PMID: 28899949 PMCID: PMC5679100 DOI: 10.1530/ERC-17-0199
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