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

Eleonora Lapi, Silvia Di Agostino, Sara Donzelli, Hilah Gal, Eytan Domany, Gideon Rechavi, Pier Paolo Pandolfi, David Givol, Sabrina Strano, Xin Lu, Giovanni Blandino

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)803-814
Number of pages12
JournalMolecular Cell
Volume32
Issue number6
DOIs
Publication statusPublished - Dec 26 2008

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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