The mechanism by which viral and cellular transcription activators regulate the processivity of the transcription elongation complex during RNA chain elongation, and in response to extra-cellular stimuli leading to regulated levels of RNA synthesis will be investigated in this proposal. Transcriptional regulation studies have primarily focused on the initiation step of transcription and relatively less is known about the following post-initiation (elongation) events. In recent years, studies have implicated transcription elongation in human tumorigenesis. Several genes implicated in pathogenesis of malignancies are regulated at the level of elongation and two elongation factors have been discovered that appear to play a role in cancer. The transcription elongation complex is a potential target for many transcriptional activators that may act to increase its processivity mediated by unique transcription elongation (factor)s. In this project, gene expression studies model viral and cellular g3ene promoters will be employed to, (i) investigate the stimulation of transcription elongation by the viral trans-activator protein VP16 which is a prototypic eukaryotic activator, and to evaluate the role in elongation for the cellular c-Myb oncoprotein which is a transcriptional activator implicated in human malignant disease; and the glucocorticoid receptor (GR) trans-activator protein also implicated in tumorigenesis, and (ii) study the hypothesis that specific extra-cellular signals mediated by signal transduction pathways lead to the synthesis or activation of latent novel nuclear elongation factors that interact with the transcriptional activators at the elongation stage of transcription, leading to superactivated level of transcription. Genetic and biochemical approaches, and mammalian cell screens using sensitive gene-reporter systems will be undertaken to clone novel regulatory elongation factors that mediate stimulation of transcription elongation by these activators, and to evaluate the role of these factors in cell proliferation and cancer. Excessive transcription and synthesis of target gene products has been implicated in tumorigenesis and, therefore, findings from this project will provide further understanding of transcriptional deregulation pf genes that is characteristic of tumor cells, as well as for transcriptional activity of viruses associated with formation of tumors in infected humans. The long-term objective of this proposal is to identify and isolate unique components of the transcription complex involved in cellular and viral transcription that may potentially serve as molecular targets for novel anti-viral and anti-cancer approaches.
Showing the most recent 10 out of 27 publications
