Document Detail


Ubiquitylation of p53 by the APC/C inhibitor Trim39.
MedLine Citation:
PMID:  23213260     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.
Authors:
Liguo Zhang; Nai-Jia Huang; Chen Chen; Wanli Tang; Sally Kornbluth
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-12-04
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-19     Completed Date:  2013-02-28     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20931-6     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs
Apoptosis
Carrier Proteins / chemistry*
Cell Cycle
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
DNA Replication
Flow Cytometry / methods
G1 Phase
Humans
Protein Binding
RNA, Small Interfering / metabolism
Tumor Suppressor Protein p53 / metabolism
Ubiquitin / chemistry*
Ubiquitin-Protein Ligase Complexes / metabolism*
Ubiquitination*
Grant Support
ID/Acronym/Agency:
R01 CA102707/CA/NCI NIH HHS; R01 CA102707/CA/NCI NIH HHS; T32 CA059365/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/CDKN1A protein, human; 0/Carrier Proteins; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/RNA, Small Interfering; 0/TP53 protein, human; 0/TRIM39 protein, human; 0/Tumor Suppressor Protein p53; 0/Ubiquitin; EC 6.3.2.19/Ubiquitin-Protein Ligase Complexes; EC 6.3.2.19/anaphase-promoting complex
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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