期刊
MOLECULAR BIOLOGY OF THE CELL
卷 20, 期 7, 页码 1891-1902出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-08-0818
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资金
- Commissariat a l'Energie Atomique-Direction des Relations Internationales (CEA-DRI)
- Fondation pour la Recherche Medicale (F.R.M.)
- l'Association pour la Recherche sur le Cancer (ARC)
- Agence Nationale de la Recherche
- National Institutes of Health [CA101810, CA108947]
Several regulatory proteins control cell cycle progression. These include Emi1, an anaphase-promoting complex (APC) inhibitor whose destruction controls progression through mitosis to G1, and p21(WAF1), a cyclin-dependent kinase (CDK) inhibitor activated by DNA damage. We have analyzed the role of p21(WAF1) in G2-M phase checkpoint control and in prevention of polyploidy after DNA damage. After DNA damage, p21(+/+) cells stably arrest in G2, whereas p21(-/-) cells ultimately progress into mitosis. We report that p21 down-regulates Emi1 in cells arrested in G2 by DNA damage. This down-regulation contributes to APC activation and results in the degradation of key mitotic proteins including cyclins A2 and B1 in p21(+/+) cells. Inactivation of APC in irradiated p21(+/+) cells can overcome the G2 arrest. siRNA-mediated Emi1 down-regulation prevents irradiated p21(-/-) cells from entering mitosis, whereas concomitant down-regulation of APC activity counteracts this effect. Our results demonstrate that Emi1 down-regulation and APC activation leads to stable p21-dependent G2 arrest after DNA damage. This is the first demonstration that Emi1 regulation plays a role in the G2 DNA damage checkpoint. Further, our work identifies a new p21-dependent mechanism to maintain G2 arrest after DNA damage.
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