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施前PI课题组在Molecular Cell发表论文

发表时间:2010-05-28  |  阅读次数:367次  |  字体大小 [ ]

528日,我院全职PI施前老师课题组与哈佛医学院联合,在Mol CellIF12.6)发表重要研究论文,获得抑癌基因PHLPP磷酸酶诱导癌细胞凋亡的新机理。

在某些乳腺癌及脑胶质母细胞瘤中,PHLPP1PHLPP2通过去磷酸化使Akt失活来行使其抑癌功能。我们发现,PHLPPs在不依赖于Akt的情况下,能诱导胃肠道肿瘤细胞产生凋亡。对这一现象背后的全新机理的研究鉴定出Mst1作为PHLPPs的结合伴侣。PHLPPs通过去磷酸化Mst1T387抑制位点来激活Mst1及其下游效应蛋白p38JNK,进而诱导凋亡。Mst1T387位点又可以被Akt磷酸化。这样一来PHLPPsAktMst1三者构成了一个自动抑制的三角循环,从而可以根据细胞类型和生理背景来精细调控细胞凋亡与增殖之间的平衡。

PHLPPsMst1Akt都是细胞凋亡和增殖过程中重要的激酶和磷酸酶。近来,科学界已经认识到了在癌症中针对AktMst1/Hippo信号途径进行治疗的潜力。然而控制它们在体内行使功能的具体机理仍未阐明。我们鉴定出Mst1既是PHLPPs的相互作用蛋白,又是PHLPPs行使诱导凋亡功能的关键介导因子。这些发现表明PHLPPs既可以直接激活Mst1诱导凋亡,也可以通过使Akt失活来激活Mst1进而诱导凋亡。我们的研究为更好的癌症治疗提供了一个新的策略,即通过AktMst1信号途径来促进癌细胞的凋亡或生长抑制。

In today’s on-line version of “Molecular Cell”, Professor Qian Shi’s group, in collaboration with a group in Harvard Medical School, published a research report detailing a novel mechanism of tumor suppressor PHLPP in inducing cell apoptosis.

PHLPP1 and PHLPP2 phosphatases exert their tumor suppressing functions by dephosphorylation and inactivation of Akt in several breast cancer and glioblastoma cells. In this study, we showed that PHLPPs induce apoptosis in GI tract cancer cells independent of Akt. A search for novel pathways identified Mst1 as a binding partner that interacts with PHLPPs both in vivo and in vitro. PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate   Mst1 and its downstream effectors, p38, JNK to induce apoptosis. The same T387 site can be phosphorylated by Akt. Thus, PHLPP, Akt and Mst1 create an auto-inhibitory triangle that controls the fine balance of apoptosis and proliferation that is cell type and context dependent.

PHLPPs, Mst1 and Akt are important phosphatases and kinases that contribute to apoptosis and proliferation. The therapeutic potential of targeting the Akt or Mst1/Hippo pathway in cancer has recently been recognized; however, detailed mechanisms that control in vivo function remains elusive. Our study identifies Mst1 as a binding partner of PHLPPs and a critical mediator of PHLPPs’ apoptotic function. These findings suggest that PHLPPs induce apoptosis through direct activation of Mst1 or activation of Mst1 via inhibition of Akt. Our results provide a novel strategy to enhance treatment of cancer that utilizes both the Akt and Mst1 pathway by promoting apoptosis or growth arrest.

 

Paper Link: http://www.cell.com/molecular-cell/abstract/S1097-2765(10)00323-0#Summary

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