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J. Biol. Chem., Vol. 279, Issue 2, 1482-1490, January 9, 2004

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NF-B Promotes Survival during Mitotic Cell Cycle Arrest^*

Pratibha Mistry, Karl Deacon¶, Sharad Mistry, Jonathan Blank, and Rajnikant Patel||

From the Department of Biochemistry and the Department of Cell Physiology and Pharmacology, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom

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-B and induction of NF-B-dependent gene expression. However, the functional consequence of NF-B activation has remained unclear. Evidence has accumulated to suggest that NF-B 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-B and test the hypothesis that the induction of NF-B 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 IKK and IKK; the phosphorylation, ubiquitination, and degradation of IB; the translocation of native p65 (RelA) into the nucleus; and increased NF-B transcriptional activity. By inhibiting either the activation of the IKKs or the degradation of IB, we find that the level of apoptosis is significantly increased in the mitotically arrested cells. Inhibition of NF-B signaling in the nonmitotic cells did not affect their survival. We establish that although NF-B 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-B may regulate the transcription of one or more antiapoptotic proteins that may regulate cell survival during mitotic cell cycle arrest.

Received for publication, September 22, 2003

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: AstraZeneca R&D Charnwood, Bakewell Rd., Loughborough, Leicestershire LE11 5RH, United Kingdom.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, University of Leicester, University Rd., Leicester LE1 7RH, United Kingdom. Tel.: 44-0116-252-2740; Fax: 44-0116-252-3699; E-mail: rp31{at}le.ac.uk.

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