Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner.
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DOI：
10.1016/j.cell.2010.12.020
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发表时间：
2011-01-21
期刊：
影响因子：
64.5
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
--
作者：
Song MS;Carracedo A;Salmena L;Song SJ;Egia A;Malumbres M;Pandolfi PP
PTEN是一种经常突变的肿瘤抑制基因，其通过磷酸肌醇-3，4，5-三磷酸的去磷酸化来对抗PI 3 K-AKT途径。最近，发现PTEN的核区室化是其肿瘤抑制活性的关键组分，然而其核功能仍然不清楚。在这里，我们表明，核PTEN与APC/C相互作用，促进APC/C与CDH 1的关联，从而增强APC-CDH 1复合物的肿瘤抑制活性。我们发现，核排斥，而不是磷酸酶失活的PTEN损害APC-CDH 1。PTEN的这种核功能为由急性PTEN损失引起的故障安全细胞衰老反应和催化失活的PTEN的肿瘤抑制活性提供了直接的机制解释。重要的是，我们证明了PTEN突变体和PTEN无效状态不是同义的，因为它们对APC-CDH 1靶点如PLK 1和Aurora激酶的药理学抑制具有不同的敏感性。这一发现确定了癌症患者分层的策略，从而优化了靶向治疗。
PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K-AKT pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor suppressive activity, however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor suppressive activity of catalytically-inactive PTEN. Importantly, we demonstrate that PTEN-mutant and PTEN-null states are not synonymous since they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora Kinases. This finding identifies a strategy for cancer patient stratification and thus, optimization of targeted therapies.
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影响因子：
7.3
作者：
Chen Z;Carracedo A;Lin HK;Koutcher JA;Behrendt N;Egia A;Alimonti A;Carver BS;Gerald W;Teruya-Feldstein J;Loda M;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
8.8
作者：
Gray, IC;Stewart, LMD;Phillips, SMA;Hamilton, JA;Gray, NE;Watson, GJ;Spurr, NK;Snary, D
通讯作者：
Snary, D
影响因子：
64.5
作者：
Bassermann, Florian;Frescas, David;Guardavaccaro, Daniele;Busino, Luca;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
全基因组的RNAi筛查鉴定了与RAS癌基因的多种合成致死相互作用。
影响因子：
64.5
作者：
Luo J;Emanuele MJ;Li D;Creighton CJ;Schlabach MR;Westbrook TF;Wong KK;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
9.2
作者：
Lenart, Peter;Petronczki, Mark;Peters, Jan-Michael
通讯作者：
Peters, Jan-Michael