Autophagic degradation of the inhibitory p53 isoform Δ133p53α as a regulatory mechanism for p53-mediated senescence

Nat Commun. 2014 Aug 21;5:4706. doi: 10.1038/ncomms5706.

Abstract

Δ133p53α, a p53 isoform that can inhibit full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. Here we demonstrate that, unlike full-length p53, Δ133p53α is degraded by autophagy during replicative senescence. Pharmacological inhibition of autophagy restores Δ133p53α expression levels in replicatively senescent fibroblasts, without affecting full-length p53. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also restores Δ133p53α expression. The chaperone-associated E3 ubiquitin ligase STUB1, which is known to regulate autophagy, interacts with Δ133p53α and is downregulated at replicative senescence. The siRNA knockdown of STUB1 in proliferating, early-passage fibroblasts induces the autophagic degradation of Δ133p53α and thereby induces senescence. Upon replicative senescence or STUB1 knockdown, Δ133p53α is recruited to autophagosomes, consistent with its autophagic degradation. This study reveals that STUB1 is an endogenous regulator of Δ133p53α degradation and senescence, and identifies a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Androstadienes / pharmacology
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Beclin-1
  • Cells, Cultured
  • Cellular Senescence / physiology*
  • Cycloheximide / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Protein Isoforms / metabolism
  • RNA, Small Interfering
  • Sequestosome-1 Protein
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Wortmannin

Substances

  • Adaptor Proteins, Signal Transducing
  • Androstadienes
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • MAP1LC3B protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Protein Isoforms
  • RNA, Small Interfering
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Cycloheximide
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases
  • Wortmannin