Diabetes, including type 1 (T1D) and type 2 (T2D) diabetes, is a major public health problem, costing over $100 billion annually in related health care. Diabetes eventually results from an inadequate number of functional beta cells. Regeneration or proliferation of human beta cells is extremely slow and inefficient in diabetic conditions, presenting a great hurdle to regenerate beta cells for ameliorating diabetes. In this regard, mutations in the multiple endocrine neoplasia type 1 gene (MEN1), which encodes the nuclear protein menin, is the only genetically proven means to effectively increase proliferation of beta cells in humans. Menin is physiologically inhibited to increase beta cell proliferation to prevent gestational diabetes. Our recent findings demonstrate that acute Men1 excision reverses pre-existing hyperglycemia in mice fed with high-fat diet (HFD). However, it is not well understood how inhibition of menin leads to increased beta cell regeneration. Recently, we helped solve the co-crystal structure of menin and JunD, and found that menin harbors a deep pocket for binding to JunD and inhibits JunD phosphorylation. Moreover, both menin and JunD bind to the promoter of the endogenous cyclin D1 gene, a crucial proliferation factor in beta cells. Furthermore, menin was found to interact with a histone arginine methyltransferase, leading to suppression of expression of other pro-proliferative genes and Hedgehog (Hh) signaling, and a pro-proliferative pathway. Thus, it is plausible to hypothesize that menin normally suppresses expression of cyclin D1 via repressing JunD, and also represses other proliferative genes and Hh signaling, in concert with histone arginine methyltransferase, to suppress beta cell regeneration. To test these hypotheses, three aims are proposed:
Aim 1. Investigate how menin controls expression of cyclin D1 via regulating JunD.
Aim 2. Examine the role of the histone arginine methyltransferase in controlling gene expression, beta cell regeneration, and glucose tolerance in mouse models.
Aim 3. Investigate menin-mediated regulation of Hh signaling in controlling beta cell regeneration. These studies will likely unravel novel mechanisms of beta cell regeneration, paving the way to develop a novel menin pathway-based therapy to treat diabetes.
Diabetes, including type 1 (T1D) and type 2 (T2D) diabetes, is a major threat to public health, costing over $100 billion annually for the related health care expense. Diabetes eventually results from an inadequate number of functional beta cells. Our proposed study to identify novel pathways regulating beta cell regeneration will likely lead to innovative therapeutic strategies to treat diabetes.
|Ma, Jian; Matkar, Smita; He, Xin et al. (2018) FOXO family in regulating cancer and metabolism. Semin Cancer Biol 50:32-41|
|Wang, Lei; Matkar, Smita; Xie, Gengchen et al. (2017) BRD4 inhibitor IBET upregulates p27kip/cip protein stability in neuroendocrine tumor cells. Cancer Biol Ther 18:229-236|
|Feng, Zijie; Ma, Jian; Hua, Xianxin (2017) Epigenetic regulation by the menin pathway. Endocr Relat Cancer 24:T147-T159|
|Feng, Zijie; Wang, Lei; Sun, Yanmei et al. (2017) Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase. Cancer Res 77:401-411|
|Muhammad, Abdul Bari; Xing, Bowen; Liu, Chengyang et al. (2017) Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB. Am J Physiol Endocrinol Metab 313:E148-E166|
|Matkar, Smita; An, Chiying; Hua, Xianxin (2017) Kinase inhibitors of HER2/AKT pathway induce ERK phosphorylation via a FOXO-dependent feedback loop. Am J Cancer Res 7:1476-1485|
|He, Xin; Wang, Lei; Yan, Jizhou et al. (2016) Menin localization in cell membrane compartment. Cancer Biol Ther 17:114-22|
|Matkar, Smita; Sharma, Paras; Gao, Shubin et al. (2015) An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis. Cancer Cell 28:472-485|
|Gurung, Buddha; Muhammad, Abdul Bari; Hua, Xianxin (2014) Menin is required for optimal processing of the microRNA let-7a. J Biol Chem 289:9902-8|
|Matkar, Smita; Katona, Bryson W; Hua, Xianxin (2014) Harnessing the hidden antitumor power of the MLL-AF4 oncogene to fight leukemia. Cancer Cell 25:411-3|
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