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Molecular and Cellular Biology, August 2005, p. 6899-6911, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.6899-6911.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

PTEN Represses RNA Polymerase I Transcription by Disrupting the SL1 Complex{dagger}

Cheng Zhang,1 Lucio Comai,2 and Deborah L. Johnson1*

Department of Biochemistry and Molecular Biology,1 Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine and Norris Comprehensive Cancer Center, 2011 Zonal Avenue, Los Angeles, California 900332

Received 31 March 2005/ Returned for modification 4 May 2005/ Accepted 18 May 2005

PTEN is a tumor suppressor whose function is frequently lost in human cancer. It possesses a lipid phosphatase activity that represses the activation of PI3 kinase/Akt signaling, leading to decreased cell growth, proliferation, and survival. The potential for PTEN to regulate transcription of the large rRNAs by RNA polymerase I (RNA Pol I) was investigated. As increased synthesis of rRNAs is a hallmark of neoplastic transformation, the ability of PTEN to control the transcription of rRNAs might be crucial for its tumor suppressor function. The expression of PTEN in PTEN-deficient cells represses RNA Pol I transcription, while decreasing PTEN expression enhances transcription. PTEN-mediated repression requires its lipid phosphatase activity and is independent of the p53 status of the cell. This event can be uncoupled from PTEN's ability to regulate the cell cycle. RNA Pol I is regulated through PI3 kinase/Akt/mammalian target of rapamycin/S6 kinase, and the expression of constitutively activated S6 kinase is able to abrogate transcription repression by PTEN. No change in the expression of the RNA Pol I transcription components, upstream binding factor or SL1, was observed upon PTEN expression. However, chromatin immunoprecipitation assays demonstrate that PTEN differentially reduces the occupancy of the SL1 subunits on the rRNA gene promoter. Furthermore, PTEN induces dissociation of the SL1 subunits. Together, these results demonstrate that PTEN represses RNA Pol I transcription through a novel mechanism that involves disruption of the SL1 complex.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine and Norris Comprehensive Cancer Center, 2011 Zonal Avenue, HMR-600, Los Angeles, CA 90033. Phone: (323) 442-1446. Fax: (323) 442-1224. E-mail: johnsond{at}usc.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2005, p. 6899-6911, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.6899-6911.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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