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 Previous Article

Molecular and Cellular Biology, June 2008, p. 4204-4214, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.01912-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

PTEN Represses RNA Polymerase III-Dependent Transcription by Targeting the TFIIIB Complex{triangledown}

Annette Woiwode,1 Sandra A. S. Johnson,1 Shuping Zhong,1 Cheng Zhang,1 Robert G. Roeder,2 Martin Teichmann,3 and Deborah L. Johnson1*

Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine and the Norris Comprehensive Cancer Center, Los Angeles, California 90033,1 Rockefeller University, New York, New York 10065,2 Institut Européen de Chimie et Biologie, Université Bordeaux 2 Victor Ségalen, Pessac F-33607, France3

Received 23 October 2007/ Returned for modification 2 January 2008/ Accepted 25 March 2008

PTEN, a tumor suppressor whose function is frequently lost in human cancers, possesses a lipid phosphatase activity that represses phosphatidylinositol 3-kinase (PI3K) signaling, controlling cell growth, proliferation, and survival. The potential for PTEN to regulate the synthesis of RNA polymerase (Pol) III transcription products, including tRNAs and 5S rRNAs, was evaluated. The expression of PTEN in PTEN-deficient cells repressed RNA Pol III transcription, whereas decreased PTEN expression enhanced transcription. Transcription repression by PTEN was uncoupled from PTEN-mediated effects on the cell cycle and was independent of p53. PTEN acts through its lipid phosphatase activity, inhibiting the PI3K/Akt/mTOR/S6K pathway to decrease transcription. PTEN, through the inactivation of mTOR, targets the TFIIIB complex, disrupting the association between TATA-binding protein and Brf1. Kinetic analysis revealed that PTEN initially induces a decrease in the serine phosphorylation of Brf1, leading to a selective reduction in the occupancy of all TFIIIB subunits on tRNALeu genes, whereas prolonged PTEN expression results in the enhanced serine phosphorylation of Bdp1. Together, these results demonstrate a new class of genes regulated by PTEN through its ability to repress the activation of PI3K/Akt/mTOR/S6K signaling.

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

{triangledown} Published ahead of print on 7 April 2008.

Molecular and Cellular Biology, June 2008, p. 4204-4214, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.01912-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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