Journal
CELL METABOLISM
Volume 25, Issue 4, Pages 868-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2017.02.004
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Funding
- NIH [RO1 DK67536]
- Japan Society for the Promotion of Science (JSPS) [26-604]
- Uehara Memorial Foundation [201540024]
- JDRF [3-APF-2014-182-A-N]
- [RO1 DK103215]
- [P30 DK036836]
- [UC4 DK104167]
- Grants-in-Aid for Scientific Research [16H05329] Funding Source: KAKEN
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Investigation of cell-cycle kinetics in mammalian pancreatic beta cells has mostly focused on transition from the quiescent (G0) to G1 phase. Here, we report that centromere protein A (CENP-A), which is required for chromosome segregation during the M-phase, is necessary for adaptive beta cell proliferation. Receptor-mediated insulin signaling promotes DNA-binding activity of FoxM1to regulate expression of CENP-A and polo-like kinase-1 (PLK1) by modulating cyclin-dependent kinase-1/2. CENP-A deposition at the centromere is augmented by PLK1 to promote mitosis, while knocking down CENP-A limits beta cell proliferation and survival. CENP-A deficiency in beta cells leads to impaired adaptive proliferation in response to pregnancy, acute and chronic insulin resistance, and aging in mice. Insulin-stimulated CENP-A/PLK1 protein expression is blunted in islets from patients with type 2 diabetes. These data implicate the insulin-FoxM1/PLK1/CENP-A pathway-regulated mitotic cell-cycle progression as an essential component in the b cell adaptation to delay and/or prevent progression to diabetes.
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