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Cell Cycle, Cell Death, and Senescence

Enhanced G₂-M Arrest by Nuclear Factor-B-Dependent p21^waf1/cip1 Induction

¹ Cancer Biology Program, ² Molecular and Cellular Pharmacology, and ³ Department of Pharmacology, University of Wisconsin-Madison, Madison, Wisconsin

Requests for reprints: Shigeki Miyamoto, Department of Pharmacology, University of Wisconsin, 301 Service Memorial Institute, 1300 University Avenue, Madison, WI 53706. Phone: 608-262-9281; Fax: 608-262-1257. E-mail: smiyamot{at}wisc.edu

The transcription factor nuclear factor-B (NF-B) regulates cell survival pathways, but the molecular mechanisms involved are not completely understood. Here, we developed a NF-B reporter cell system derived from CEM T leukemic cells to monitor the consequences of NF-B activation following DNA damage insults. Cells that activated NF-B in response to ionizing radiation or etoposide arrested in the G₂-M phase for a prolonged time, which was followed by increased cell cycle reentry and survival. In contrast, those that failed to activate NF-B underwent transient G₂-M arrest and extensive cell death. Importantly, p21^waf1/cip1 was induced in S-G₂-M phases in a NF-B-dependent manner, and RNA interference of this cell cycle regulator reduced the observed NF-B-dependent phenotypes. Thus, cell cycle–coupled induction of p21^waf1/cip1 by NF-B represents a resistance mechanism in certain cancer cells.

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