PML, YAP, and p73 Are Components of a Proapoptotic Autoregulatory Feedback Loop Academic Article uri icon

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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.

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

publication date

  • December 2008

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