Negative regulation of RNA polymerase III transcription

Cancer is characterized by uncontrolled growth and the spread of abnormal cells. The requirement of all cancer cells for tRNA and rRNA to maintain uncontrolled growth implicates RNA polymerase III as a critical player in the regulation of proliferation in tumor cells. RNA polymerase III is responsible for transcribing many of the small structural RNA molecules required for cellular growth, thereby, regulating the biosynthetic capacity of a cell. RNA polymerase III transcribes genes involved in processing (U6 snRNA) and translation (tRNAs) and influences the growth rate of a cell. TFIIIB is required for proper transcription initiation and in higher eukaryotes, at least two forms of TFIIIB have been identified. Gene internal promoters, such as VAI, require a form of TFIIIB consisting of TBP, Bdp1 and Brf1, whereas gene external promoters, such as U6 snRNA, require a TFIIIB complex containing TBP, Bdp1, and Brf2. It has been established that RNA polymerase III transcription is often deregulated in cancer cells and TFIIIB, necessary for accurate initiation by RNA polymerase III, is a molecular target of deregulation by tumor suppressors and oncogenic products.;The emphasis of my research has been on the negative regulation of RNA pol III transcription in cancer cells. At the end of this thesis, I will have demonstrated the following: (1) the Brf1 and Brf2 subunits of TFIIIB are differentially expressed in cancer cells. (2) RNA pol III transcription is negatively regulated by the tumor suppressor PTEN, and lastly, (3) RNA pol III transcription is differentially regulated by the chemopreventative agent resveratrol in a cell type specific manner.