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Autophagic degradation of the inhibitory p53 isoform Δ133p53α as a regulatory mechanism for p53-mediated senescence
I. Horikawa, K. Fujita, LM. Jenkins, Y. Hiyoshi, AM. Mondal, B. Vojtesek, DP. Lane, E. Appella, CC. Harris,
Language English Country England, Great Britain
Document type Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 2010
Nature Open Access
from 2010-12-01
PubMed Central
from 2012
Europe PubMed Central
from 2012
ProQuest Central
from 2010-01-01
Medline Complete (EBSCOhost)
from 2012-11-01
Health & Medicine (ProQuest)
from 2010-01-01
ROAD: Directory of Open Access Scholarly Resources
from 2010
Springer Nature OA/Free Journals
from 2010-12-01
PubMed
25144556
DOI
10.1038/ncomms5706
Knihovny.cz E-resources
- MeSH
- Adaptor Proteins, Signal Transducing genetics metabolism MeSH
- Androstadienes pharmacology MeSH
- Autophagy drug effects physiology MeSH
- Cycloheximide pharmacology MeSH
- Fibroblasts drug effects metabolism MeSH
- Gene Knockdown Techniques MeSH
- Cells, Cultured MeSH
- Humans MeSH
- RNA, Small Interfering MeSH
- Membrane Proteins genetics metabolism MeSH
- Tumor Suppressor Protein p53 genetics metabolism MeSH
- Protein Isoforms metabolism MeSH
- Microtubule-Associated Proteins genetics metabolism MeSH
- Apoptosis Regulatory Proteins genetics metabolism MeSH
- Cellular Senescence physiology MeSH
- Ubiquitin-Protein Ligases genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Intramural MeSH
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.
References provided by Crossref.org
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