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J. Biol. Chem., Vol. 279, Issue 39, 40511-40520, September 24, 2004

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Aberrant Regulation of Survivin by the RB/E2F Family of Proteins^*

Yuying Jiang, Harold I. Saavedra, Michael P. Holloway, Gustavo Leone, and Rachel A. Altura¶||

From the Columbus Children's Research Institute, the ^¶Department of Pediatrics, and the Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics and Department of Molecular Genetics, College of Medicine and Public Health, Ohio State University, Columbus, Ohio 43210

Survivin is a putative oncogene that is aberrantly expressed in cancer cells. It has been hypothesized to play a central role in cancer progression and resistance to therapy in diverse tumor types. Although some of the transcriptional processes regulating its expression have been established, the diversity of genes that may be controlling the levels of its expression in both normal cells as well as in cancer cells has not been fully explored. The most common genetically mutated pathways in human malignancies are the p53 tumor suppressor pathway and the RB/E2F pathway. Both of these pathways, when intact, provide essential checkpoints in the maintenance of normal cell growth and protect the cell from DNA damage. Using non-transformed embryonic fibroblasts, we provide evidence of a molecular link between the regulation of survivin transcription and the RB/E2F family of proteins. We demonstrate that both pRB and p130 can interact with the survivin promoter and can repress survivin transcription. We also show that the E2F activators (E2F1, E2F2, and E2F3) can bind to the survivin promoter and induce survivin transcription. Genetically modified cells that harbor deletions in various members of the RB/E2F family confirm our data from the wild-type cells. Our findings implicate several members of the RB/E2F pathway in an intricate mechanism of survivin gene regulation that, when genetically altered during the process of tumorigenesis, may function within cancer cells to aberrantly alter survivin levels and enhance tumor progression.

Received for publication, April 23, 2004 , and in revised form, July 7, 2004.

^* This work was supported in part by the Hope Street Kids Foundation, by Children's Research Institute at Columbus Children's Hospital, and by Institutional Research Grant IRG-98-278-01 from the American Cancer Society. 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.

^|| To whom correspondence should be addressed: Columbus Children's Research Institute, R II 5021, 700 Children's Dr., Columbus, OH 43205. Tel.: 614-722-5413; Fax: 614-722-5895; E-mail: Alturar{at}pediatrics.ohio-state.edu.

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