Repression of RNA polymerase III-dependent transcription by the tumor suppressorsp53 and PTEN

For cells to grow and proliferate they must be capable of protein synthesis. As RNA polymerase (pol) III transcription products are required for protein synthesis, RNA pol III transcriptional activity is tightly linked to the rate of cell growth. High levels of RNA pol III transcription products are seen in transformed and tumor cells, suggesting that aberrant regulation of RNA pol III transcription contributes to transformation and tumorigenesis. The tumor suppressor p53 represses RNA pol III transcription by directly targeting the RNA pol III transcription factor complex TFIIIB which consists of TBP, Brf1, and Bdp1. TBP and Brf1 associate to form a stable complex while Bdp1 associates reversibly with the complex. Our studies determined that p53 mediates repression of RNA pol III transcription by directly targeting TBP which is limiting for RNA pol III transcription in the presence but not the absence of p53 expression. In contrast, Brf1 is not limiting for RNA pol III transcription. Although p53 binds to the TBP/Brf1 complex, it does not disrupt the complex. As p53 mediates repression of RNA pol III transcription, we determined whether another tumor suppressor, PTEN, represses RNA pol III transcription. Whereas p53 is a transcription factor that functions in the nucleus, PTEN is a lipid phosphatase that functions largely in the cytoplasm. The lipid phosphatase activity of PTEN directly antagonizes the PI-3 kinase (PI3K) signal transduction pathway. We determined that PTEN mediates repression of RNA pol III transcription via its lipid phosphatase activity. We also determined that the PI3K pathway regulates RNA pol III transcription; therefore, we suggest that antagonism of the PI3K pathway is one mechanism by which PTEN mediates repression of RNA pol III transcription. We also determined the effect of PTEN on TFIIIB. PTEN was found to disrupt the TBP/Brf1 complex with this disruption correlating with a PTEN-mediated decrease in Brf1 serine phosphorylation. PTEN was also found to decrease the occupancy of TFIIIB on a tRNA gene. We suggest that the PTEN-mediated decrease in Brf1 serine phosphorylation leads to disruption of the TBP/Brf1 complex which in turn leads to a decrease in TFIIIB occupancy on a tRNA gene.