title: Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic β Cell Proliferation.
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.
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Fernandez
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Takatani
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Abdelfattah
authors.initials: A
authors.lastname: El Ouaamari
authors.affiliation: Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Jungtrakoon
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Okawa
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yi
authors.affiliation: Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.affiliation: Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA. Electronic address: rohit.kulkarni@joslin.harvard.edu.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D017209:Apoptosis; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002503:Centromere / Q000378:metabolism; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D000072278:Forkhead Box Protein M1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D000097869:Polo-Like Kinase 1
chemical_list: D001324:Autoantigens; D018797:Cell Cycle Proteins; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D000072278:Forkhead Box Protein M1; D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011972:Receptor, Insulin; D000097869:Polo-Like Kinase 1; C000619700:CENPA protein, human; C000619701:Cenpa protein, mouse
keywords: CENP-A; FoxM1; M-phase; PLK1; apoptosis; cell cycle; cell proliferation; human islets; insulin receptor signaling; type 2 diabetes; β