CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion.
Cell Cycle
; 12(18): 3063-9, 2013 Sep 15.
Article
en En
| MEDLINE
| ID: mdl-23974099
ABSTRACT
CDKN1A (p21) and CDKN2A (p16) inhibit CDK4/6, initiating senescence. According to our view on senescence, the role of p21 and p16 is to cause cell cycle arrest, whereas MTOR (mechanistic target of rapamycin) drives geroconversion to senescence. Recently we demonstrated that one of the markers of p21- and p16-initiated senescence is MEK-dependent hyper-elevation of cyclin D1. We noticed that a synthetic inhibitor of CDK 4/6 (PD0332991) also induced cyclin D1-positive senescence. We demonstrated that PD0332991 and p21 caused almost identical senescence phenotypes. p21, p16, and PD0332991 do not inhibit MTOR, and rapamycin decelerates geroconversion caused by all 3 molecules. Like p21, PD0332991 initiated senescence at any concentration that inhibited cell proliferation. This confirms the notion that a mere arrest in the presence of active MTOR may lead to senescence.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidor p16 de la Quinasa Dependiente de Ciclina
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Quinasa 4 Dependiente de la Ciclina
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Quinasa 6 Dependiente de la Ciclina
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina
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Serina-Treonina Quinasas TOR
Límite:
Humans
Idioma:
En
Revista:
Cell Cycle
Año:
2013
Tipo del documento:
Article