Document Detail


The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity.
MedLine Citation:
PMID:  23085759     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The Cullin4A (cul4A)-dependent ligase (CDL4A) E3 has been implicated in a variety of biological processes, including cell cycle progression and DNA damage response. Remarkably, CDL4A exerts its function through both proteolytic and non-proteolytic events. Here, we show that the p53 family member p73 is able to interact with the CDL4A complex through its direct binding to the receptor subunit DNA-binding protein 1 (DDB1). As a result, the CDL4A complex is able to monoubiquitylate p73. Modification of p73 by CDL4A-mediated ubiquitylation does not affect p73 protein stability, but negatively regulates p73-dependent transcriptional activity. Indeed, genetic or RNA interference-mediated depletion of DDB1 induces the expression of several p73 target genes in a p53-independent manner. In addition, by exploiting a bioinformatic approach, we found that elevated expression of Cul4A in human breast carcinomas is associated with repression of p73 target genes. In conclusion, our findings add a novel insight into the regulation of p73 by the CDL4A complex, through the inhibition of its transcriptional function.
Authors:
M Malatesta; A Peschiaroli; E M Memmi; J Zhang; A Antonov; D R Green; N A Barlev; A V Garabadgiu; P Zhou; G Melino; F Bernassola
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-22
Journal Detail:
Title:  Oncogene     Volume:  32     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-09-27     Completed Date:  2013-11-15     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  4721-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Breast Neoplasms / metabolism
Carcinoma / metabolism
Carrier Proteins / physiology
Cell Line
Cullin Proteins / physiology*
DNA-Binding Proteins / antagonists & inhibitors*,  metabolism,  physiology*
Female
Gene Expression Regulation, Neoplastic / physiology
HEK293 Cells
Humans
Mice
Multiprotein Complexes
Neoplasm Proteins / antagonists & inhibitors,  physiology*
Nuclear Proteins / antagonists & inhibitors*,  metabolism
Protein Binding
Protein Processing, Post-Translational
Protein Stability
Transcription, Genetic* / physiology
Tumor Suppressor Protein p53 / deficiency,  physiology
Tumor Suppressor Proteins / antagonists & inhibitors*,  metabolism
Ubiquitination
Grant Support
ID/Acronym/Agency:
2R01CA098210/CA/NCI NIH HHS; 5R01CA 118085/CA/NCI NIH HHS; MC_U132670600//Medical Research Council
Chemical
Reg. No./Substance:
0/CUL4A protein, human; 0/Carrier Proteins; 0/Cullin Proteins; 0/DDB1 protein, human; 0/DNA-Binding Proteins; 0/Multiprotein Complexes; 0/Neoplasm Proteins; 0/Nuclear Proteins; 0/RBX1 protein, human; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 0/tumor suppressor protein p73

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


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