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

被引：212

作者：

Lapi, Eleonora ^{[2
]}

Di Agostino, Silvia ^{[1
]}

Donzelli, Sara ^{[1
]}

Gal, Hilah ^{[3
,4
]}

Domany, Eytan ^{[3
]}

Rechavi, Gideon ^{[5
]}

Pandolfi, Pier Paolo ^{[6
,7
]}

Givol, David ^{[4
]}

Strano, Sabrina ^{[1
]}

Lu, Xin ^{[2
]}

Blandino, Giovanni ^{[1
]}

机构：

[1] Regina Elena Inst Canc Res, Translat Oncogenom Unit, I-00144 Rome, Italy

[2] Univ Oxford Branch, Ludwig Inst Canc Res, Oxford OX3 7DQ, England

[3] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel

[4] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[5] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Tel Hashomer, Israel

[6] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program,Dept Med, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program,Dept Pathol, Boston, MA 02115 USA

来源：

MOLECULAR CELL | 2008年 / 32卷 / 06期

关键词：

D O I：

10.1016/j.molcel.2008.11.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 p73NAP, 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.

引用

页码：803 / 814

页数：12

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