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J. Biol. Chem., Vol. 281, Issue 32, 22729-22735, August 11, 2006

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Bok, Bcl-2-related Ovarian Killer, Is Cell Cycle-regulated and Sensitizes to Stress-induced Apoptosis^*

Jose M. Rodriguez^¶||, Michele A. Glozak, Yihong Ma, and W. Douglas Cress^||1

From the Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, ^¶Cancer Biology Ph.D. Program, ^||University of South Florida, Tampa, Florida 33612

Bok/Mtd (Bcl-2-related ovarian killer/Matador) is considered a pro-apoptotic member of the Bcl-2 family. Although identified in 1997, little is known about its biological role. We have previously demonstrated that Bok mRNA is up-regulated following E2F1 overexpression. In the current work, we demonstrate that Bok RNA is low in quiescent cells and rises upon serum stimulation. To determine the mechanism underlying this regulation, we cloned and characterized the mouse Bok promoter. We find that the mouse promoter contains a conserved E2F binding site (-43 to -49) and that a Bok promoter-driven luciferase reporter is activated by serum stimulation dependent on this site. Chromatin immunoprecipitation assays demonstrate that endogenous E2F1 and E2F3 associate with the Bok promoter in vivo. Surprisingly, we find that H1299 cells can stably express high levels of exogenous Bok protein. However, these cells are highly sensitive to chemotherapeutic drug treatment. Taken together these results demonstrate that Bok represents a cell cycle-regulated pro-apoptotic member of the Bcl-2 family, which may predispose growing cells to chemotherapeutic treatment.

Received for publication, May 16, 2006

^* This work was supported by National Institutes of Health NCI Grant CA90489 (to W. D. C.), a Minority Supplement to CA090489 (to J. M. R.), Department of Defense National Functional Genomics Pilot Project 12-12990-01-01 (to W. D. C.), and the Molecular Biology, Flow Cytometry, Analytical Microscopy, and the Molecular Imaging Core Facilities of the Moffitt Cancer Institute. 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.

¹ To whom correspondence should be addressed: 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-979-6703; E-mail: cressd{at}moffitt.usf.edu.

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