Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic β Cell Proliferation

Publication date: Available online 9 March 2017
Source:Cell Metabolism
Author(s): Jun Shirakawa, Megan Fernandez, Tomozumi Takatani, Abdelfattah El Ouaamari, Prapaporn Jungtrakoon, Erin R. Okawa, Wei Zhang, Peng Yi, Alessandro Doria, Rohit N. Kulkarni
Investigation of cell-cycle kinetics in mammalian pancreatic β 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 β cell proliferation. Receptor-mediated insulin signaling promotes DNA-binding activity of FoxM1 to 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 β cell proliferation and survival. CENP-A deficiency in β 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 β cell adaptation to delay and/or prevent progression to diabetes.

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Teaser

Adaptive β cell proliferation contributes to maintenance of functional β cell mass in mouse and man. Shirakawa et al. reveal that growth factor signaling regulates mitotic cell-cycle progression through the FoxM1/PLK1/CENP-A pathway, a critical component in the β cell adaptive response.


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