Characterization of p53-mediated transcriptional regulation of c -myc and klhl26.

摘要

The p53 tumor suppressor protein reacts to a number of genotoxic and oncogenic signals. Upon activation, p53 can promote various cellular processes including cell cycle arrest, differentiation, and apoptosis via its ability to regulate the transcription of target genes. In this thesis, two of these genes, c-myc and klhl26, were examined for their regulation and physiological significance to the p53 pathway. c-myc is repressed in a number of mouse and human cell types in a p53-dependent manner. p53 binds to the c-myc gene and mediates transrepression through a mechanism that involves historic deacetylation. This repression is required for the efficient induction of G1 cell cycle arrest and differentiation by p53. As cell cycle regulation is believed to be a mechanism by which p53 mediates tumor suppression, the transcriptional repression of c-myc by p53 may restrain tumor development. In contrast to c-myc, klhl26 is transcriptionally-activated by p53. This is also associated with the binding of p53 to the klhl26 gene. klhl26 possesses prosurvival activity and confers cytoprotection against both p53-dependent and p53-independent apoptosis. The significance of this antiapoptotic function to the p53 response, however, is presently unclear. Taken together, c-myc and klhl26 are bona fide p53 target genes and their regulation impacts upon the ability of p53 to mediate various processes in the cell.