TY - JOUR
T1 - PML, YAP, and p73 Are Components of a Proapoptotic Autoregulatory Feedback Loop
AU - Lapi, Eleonora
AU - Di Agostino, Silvia
AU - Donzelli, Sara
AU - Gal, Hilah
AU - Domany, Eytan
AU - Rechavi, Gideon
AU - Pandolfi, Pier Paolo
AU - Givol, David
AU - Strano, Sabrina
AU - Lu, Xin
AU - Blandino, Giovanni
N1 - Funding Information:
We wish to thank Dr. Marius Sudol for the critical reading of the manuscript and Dr. Scott Lowe for supplying PML-promoter-luc, PML-intron-luc, and Res1,2,3mutPML-intron-luc constructs. This work was supported by the Italian Association for Cancer Research (AIRC) to S.S. and G.B., by Ministero della Sanità, by MIUR-FIRB Italy, and by European Community (EC) Active p53 and Mutant p53 consortia to G.B., X.L., and E.D. This work was partially supported by grants from the Wolfson Family Charitable Trust on Tumor Cell Diversity (E.D., D.G., and G.R.) and the Ridgefield Foundation (E.D.). This publication reflects the authors' views and not necessarily those of the European Community. The EC is not liable for any use that may be made of the information contained herein. E.L. and S.D. hold an FIRC fellowship.
PY - 2008/12/26
Y1 - 2008/12/26
N2 - 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.
AB - 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.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=57749084642&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2008.11.019
DO - 10.1016/j.molcel.2008.11.019
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AN - SCOPUS:57749084642
SN - 1097-2765
VL - 32
SP - 803
EP - 814
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -
