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PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex

Annette Woiwode1, Sandra A S Johnson, Shuping Zhong

  • 1Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine and the Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.

Molecular and Cellular Biology
|April 9, 2008
PubMed

Insights

PTEN, a tumor suppressor, represses RNA Polymerase III transcription by inhibiting the PI3K/Akt/mTOR/S6K pathway. This action is independent of cell cycle effects and p53, revealing a new regulatory mechanism in cancer.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • PTEN is a crucial tumor suppressor frequently lost in human cancers.
  • PTEN's known function involves lipid phosphatase activity, repressing phosphatidylinositol 3-kinase (PI3K) signaling to control cell growth, proliferation, and survival.

Purpose of the Study:

  • To investigate the role of PTEN in regulating RNA polymerase (Pol) III transcription.
  • To elucidate the molecular mechanisms by which PTEN affects Pol III transcription.

Main Methods:

  • PTEN expression was manipulated in PTEN-deficient cells.
  • Analysis of RNA Pol III transcription products (tRNAs, 5S rRNAs).
  • Investigation of the PI3K/Akt/mTOR/S6K pathway and TFIIIB complex involvement, including phosphorylation states of Brf1 and Bdp1.

Main Results:

  • PTEN expression repressed RNA Pol III transcription, while PTEN deficiency enhanced it.
  • Repression was independent of cell cycle effects and p53.
  • PTEN inhibited transcription via its lipid phosphatase activity, targeting the PI3K/Akt/mTOR/S6K pathway and subsequently the TFIIIB complex.
  • PTEN altered Brf1 and Bdp1 phosphorylation, affecting TFIIIB subunit occupancy on tRNA genes.

Conclusions:

  • PTEN represses RNA Pol III transcription through inhibition of the PI3K/Akt/mTOR/S6K signaling pathway.
  • This study identifies a novel class of genes regulated by PTEN via modulation of transcription factor complexes.
  • PTEN's tumor-suppressive function extends to the regulation of essential non-coding RNA synthesis.

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