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

Cell Metab. 2017 Apr 4;25(4):868-882.e5. doi: 10.1016/j.cmet.2017.02.004. Epub 2017 Mar 9.

Abstract

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.

Keywords: CENP-A; FoxM1; M-phase; PLK1; apoptosis; cell cycle; cell proliferation; human islets; insulin receptor signaling; type 2 diabetes; β.

MeSH terms

  • Animals
  • Apoptosis
  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cell Survival
  • Centromere / metabolism
  • Centromere Protein A
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA / metabolism
  • Diabetes Mellitus, Type 2 / metabolism
  • Forkhead Box Protein M1 / metabolism*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Insulin / metabolism*
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor, Insulin / metabolism
  • Signal Transduction*

Substances

  • Autoantigens
  • CENPA protein, human
  • Cell Cycle Proteins
  • Cenpa protein, mouse
  • Centromere Protein A
  • Chromosomal Proteins, Non-Histone
  • Forkhead Box Protein M1
  • Insulin
  • Proto-Oncogene Proteins
  • DNA
  • Receptor, Insulin
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1