PML, YAP, and p73 Are Components of a Proapoptotic Autoregulatory Feedback Loop

p73 has been identified as a structural and functional homolog of the tumor suppressor p53. The transcriptional coactivator Yes-associated protein (YAP) has been demonstrated to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show the existence of a proapopto...

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Bibliographic Details
Published in:Molecular cell Vol. 32; no. 6; pp. 803 - 814
Main Authors: Lapi, Eleonora, Di Agostino, Silvia, Donzelli, Sara, Gal, Hilah, Domany, Eytan, Rechavi, Gideon, Pandolfi, Pier Paolo, Givol, David, Strano, Sabrina, Lu, Xin, Blandino, Giovanni
Format: Journal Article
Language:English
Published: United States Elsevier Inc 26-12-2008
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Summary:p73 has been identified as a structural and functional homolog of the tumor suppressor p53. The transcriptional coactivator Yes-associated protein (YAP) has been demonstrated to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Here, we show the existence of a proapoptotic autoregulatory feedback loop between p73, YAP, and the promyelocytic leukemia (PML) tumor suppressor gene. We demonstrate that PML is a direct transcriptional target of p73/YAP, and we show that PML transcriptional activation by p73/YAP is under the negative control of the proto-oncogenic Akt/PKB kinase. Importantly, we find that PML and YAP physically interact through their PVPVY and WW domains, respectively, causing PML-mediated sumoylation and stabilization of YAP. Hence, we determine a mechanistic pathway in response to DNA damage that could have relevant implications for the treatment of human cancer.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2008.11.019