Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic ß Cell Proliferation.
Cell Metab
; 25(4): 868-882.e5, 2017 Apr 04.
Article
en En
| MEDLINE
| ID: mdl-28286049
ABSTRACT
Investigation of cell-cycle kinetics in mammalian pancreatic ß 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 ß 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 ß cell proliferation and survival. CENP-A deficiency in ß 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 ß cell adaptation to delay and/or prevent progression to diabetes.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autoantígenos
/
Proteínas Cromosómicas no Histona
/
Transducción de Señal
/
Proteínas Proto-Oncogénicas
/
Proteínas Serina-Treonina Quinasas
/
Proteínas de Ciclo Celular
/
Células Secretoras de Insulina
/
Proteína Forkhead Box M1
/
Insulina
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos