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, 32 (6), 803-14

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

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

Eleonora Lapi et al. Mol Cell.

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.

Comment in

  • YAP and p73: A Complex Affair
    J Downward et al. Mol Cell 32 (6), 749-50. PMID 19111652.
    In this issue of Molecular Cell, Lapi et al. (2008) demonstrate that YAP binds p73 to activate PML transcription, which in turn mediates YAP sumoylation and stabilization …

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