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The ubiquitin–protein ligase Itch regulates p73 stability
Author(s) -
Rossi Mario,
De Laurenzi Vincenzo,
Munarriz Eliana,
Green Douglas R,
Liu YunCai,
Vousden Karen H,
Cesareni Gianni,
Melino Gerry
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600444
Subject(s) - ubiquitin ligase , biology , ubiquitin , proteasome , microbiology and biotechnology , downregulation and upregulation , ddb1 , mdm2 , dna damage , transcription factor , f box protein , dna binding protein , transcription (linguistics) , protein degradation , nuclear protein , dna , apoptosis , biochemistry , gene , linguistics , philosophy
p73, a member of the p53 family of transcription factors, is upregulated in response to DNA damage, inducing cell cycle arrest and apoptosis. Besides indications that this p73 response is post‐transcriptional, little is known about the underlying molecular mechanisms of p73 protein degradation. Ubiquitination and proteasomal‐dependent degradation of p53 are regulated by its transcriptional target MDM2. However, unlike p53, p73 binds to, but is not degraded by, MDM2. Here we describe the binding of p73 to Itch, a Hect ubiquitin–protein ligase. Itch selectively binds and ubiquitinates p73 but not p53; this results in the rapid proteasome‐dependent degradation of p73. Upon DNA damage Itch itself is downregulated, allowing p73 protein levels to rise and thus interfere with p73 function. In conclusion, we have identified a key mechanism in the control of p73 protein levels both in normal as well as in stress conditions.