Abstract PR08: Autophagic degradation of Δ133p53 during replicative cellular senescence: An isoform-specific protein degradation mechanism for p53

Abstract

Abstract Δ133p53, a p53 isoform that dominant-negatively inhibits full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. We here demonstrate that, in contrast to proteasomal degradation of full-length p53, Δ133p53 is degraded by autophagy. Pharmacological inhibition of autophagy restores the reduced expression of Δ133p53 in replicatively senescent fibroblasts. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also results in restored expression of Δ133p53. The degradation of Δ133p53 via selective autophagy is indicated by its ubiquitination at the C-terminal lysine residues, its colocalization in the cytoplasm with a ubiquitin-binding protein p62/SQSTM1 and an autophagosome component LC3-II upon autophagy induction, and its stabilization by siRNA knockdown of p62/SQSTM1. A chaperone-associated E3 ubiquitin ligase STUB1, rather than MDM2, physically interacts with Δ133p53 and, consistent with the downregulation of endogenous STUB1 at replicative senescence, siRNA knockdown of STUB1 induces autophagic degradation of Δ133p53 and thereby senescence. Our data reveal that Δ133p53 degradation is controlled specifically by STUB1, rather than overall activity of autophagy. This study has identified for the first time a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence and supports the hypothesis that Δ133p53 functions at the crossroads of senescence and autophagy. This abstract is also presented as poster B19. Citation Format: Izumi Horikawa, Kaori Fujita, Lisa Miller Jenkins, Yukiharu Hiyoshi, Abdul M. Mondal, Borivoj Vojtesek, David P. Lane, Ettore Appella, Curtis C. Harris. Autophagic degradation of Δ133p53 during replicative cellular senescence: An isoform-specific protein degradation mechanism for p53. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR08.