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J. Biol. Chem., Vol. 283, Issue 4, 2353-2362, January 25, 2008

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RhoBTB2 (DBC2) Is a Mitotic E2F1 Target Gene with a Novel Role in Apoptosis^*

Scott N. Freeman^¶, Yihong Ma, and W. Douglas Cress¹

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

We have identified the RhoBTB2 putative tumor suppressor gene as a direct target of the E2F1 transcription factor. Overexpression of E2F1 led to up-regulation of RhoBTB2 at the level of mRNA and protein. This also occurred during the induction of E2F1 activity in the presence of cycloheximide, thus indicating that RhoBTB2 is a direct target. RNAi-mediated knockdown of E2F1 resulted in decreased RhoBTB2 protein expression, demonstrating that RhoBTB2 is a physiological target of E2F1. Because E2F1 primarily serves to transcribe genes involved in cell cycle progression and apoptosis, we explored whether RhoBTB2 played roles in either of these processes. We found RhoBTB2 expression highly up-regulated during mitosis, which was partially dependent on the presence of E2F1. Furthermore, overexpression of RhoBTB2 induced a short term increase in cell cycle progression and proliferation, while long term expression had a negative effect on these processes. We similarly found RhoBTB2 up-regulated during drug-induced apoptosis, with this being primarily dependent on E2F1. Finally, we observed that knockdown of RhoBTB2 levels via siRNA delayed the onset of drug-induced apoptosis. Collectively, we describe RhoBTB2 as a novel direct target of E2F1 with roles in cell cycle and apoptosis.

Received for publication, July 20, 2007 , and in revised form, November 21, 2007.

^* This work was supported in part by NCI, National Institutes of Health Grant R01 CA090489 (to W. D. C.), the Department of Interdisciplinary Oncology Research Account Fund (DIO RAF 84-15049), and the Moffitt Research Institute. Additionally, this work has been supported in part by the Molecular Biology Core, the Flow Cytometry Core, and the Analytical Microscopy Core facilities at the H. Lee Moffitt Cancer Center & Research 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.: 813-745-6703; E-mail: douglas.cress{at}moffitt.org.