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Oncogene. 2013 Sep 26;32(39):4721-6. doi: 10.1038/onc.2012.463. Epub 2012 Oct 22.

The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity.

Author information

1
Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.

Abstract

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.

PMID:
23085759
DOI:
10.1038/onc.2012.463
[Indexed for MEDLINE]

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