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J. Biol. Chem., Vol. 283, Issue 28, 19184-19191, July 11, 2008

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Enhanced RNA Polymerase III-dependent Transcription Is Required for Oncogenic Transformation^*

Sandra A. S. Johnson, Louis Dubeau, and Deborah L. Johnson¹

From the Departments of Biochemistry and Molecular Biology and Pathology and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089

RNA polymerase (pol) III transcription, responsible for the synthesis of various stable RNAs, including 5 S rRNAs and tRNAs, is regulated by oncogenic proteins and tumor suppressors. Although it is well established that RNA pol III-dependent transcription is deregulated in transformed cells and malignant tumors, it has not been determined whether this represents a cause or consequence of these processes. We show that Rat1a fibroblasts undergoing oncogenic transformation by the TATA-binding protein or c-Myc display enhanced RNA pol III transcription. Decreased expression of the RNA pol III-specific transcription factor Brf1 prevented this increase in RNA pol III transcription. Although the overall proliferation rates of these cells remained unchanged, the ability of cells to grow in an anchorage-independent manner and form tumors in mice was markedly reduced. Although overexpression of Brf1 modestly stimulated RNA pol III transcription, expression of a phosphomimic, Brf1-T145D, more significantly induced transcription. However, these increases in transcription were not sufficient to promote cellular transformation. Together, these results demonstrate that enhanced RNA pol III transcription is essential for anchorage-independent growth and tumorigenesis and that these events can be uncoupled from effects on anchorage-dependent proliferation.

Received for publication, April 15, 2008 , and in revised form, April 28, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Postdoctoral Training Grant 2 T32 CA009659 (to S. A. S. J.) and National Institutes of Health Grants CA74138 and CA108614 (to D. L. J.). 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.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Southern California, HMR-600 MC 9097, 2011 Zonal Ave., Los Angeles, CA 90089. Tel.: 323-442-1446; Fax: 323-442-1224; E-mail: johnsond{at}usc.edu.

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