NF-κB promotes survival during mitotic cell cycle arrest

被引:47
作者
Mistry, P
Deacon, K
Mistry, S
Blank, J
Patel, R
机构
[1] Univ Leicester, Dept Biochem, Leicester LE1 7RH, Leics, England
[2] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 7RH, Leics, England
关键词
D O I
10.1074/jbc.M310413200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
By activating the mitotic checkpoint, anti-microtubule drugs such as nocodazole cause mammalian cells to arrest in mitosis and then undergo apoptosis. Microtubule depolymerization is rapid and results in the activation of the transcription factor NF-kappaB and induction of NF-kappaB-dependent gene expression. However, the functional consequence of NF-kappaB activation has remained unclear. Evidence has accumulated to suggest that NF-kappaB transcriptional activity is required to suppress apoptosis. In the present study, we confirm and extend previous findings that microtubule depolymerization leads to the rapid activation of NF-kappaB and test the hypothesis that the induction of NF-kappaB regulates cell survival during mitotic cell cycle arrest in order to define its role. Using a range of functional assays, we have shown that microtubule depolymerization correlates with the activation of IKKalpha and IKKbeta; the phosphorylation, ubiquitination, and degradation of IkappaBalpha; the translocation of native p65 (RelA) into the nucleus; and increased NF-kappaB transcriptional activity. By inhibiting either the activation of the IKKs or the degradation of IkappaBalpha, we find that the level of apoptosis is significantly increased in the mitotically arrested cells. Inhibition of NF-kappaB signaling in the nonmitotic cells did not affect their survival. We establish that although NF-kappaB is activated rapidly in response to microtubule depolymerization, its cell survival function is not required until mitotic cell cycle arrest, when the mitotic checkpoint is activated and apoptosis is triggered. We conclude that NF-kappaB may regulate the transcription of one or more antiapoptotic proteins that may regulate cell survival during mitotic cell cycle arrest.
引用
收藏
页码:1482 / 1490
页数:9
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