The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway
The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway
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DOI：
10.1073/pnas.95.26.15587
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发表时间：
1998-12-22
影响因子：
11.1
通讯作者：
Sawyers, CL
中科院分区：
文献类型：
--
作者：
Wu, XY;Senechal, K;Sawyers, CL
PTEN/MMAC 1磷酸酶是一种与多种人类癌症有关的肿瘤抑制基因。在这里，我们提供的生化和功能的证据表明，PTEN/MMAC 1作为磷酸肌醇3-激酶（PI 3-激酶）/Akt途径的负调节剂。PTEN/MMAC 1损害细胞中内源性Akt的活化并抑制4 E-BP 1的磷酸化，4 E-BP 1是参与蛋白质翻译的PI 3-激酶/Akt途径的下游靶标，而催化失活的显性失活的PTEN/MMAC 1突变体增强4 E-BP 1磷酸化。此外，PTEN/MMAC 1抑制基因表达的方式是由Akt拯救，而不是PI-激酶。最后，与PTEN/MMAC 1阳性前列腺肿瘤或正常前列腺组织相比，在缺乏PTEN/MMAC 1表达的人前列腺癌细胞系和异种移植物中观察到更高水平的Akt活化。因为已知PI 3-激酶或Akt的组成性活化诱导细胞转化，所以由PTEN/MMAC 1突变引起的该途径活化的增加为其肿瘤抑制功能提供了潜在机制。
The PTEN/MMAC1 phosphatase is a tumor suppressor gene implicated in a wide range of human cancers. Here we provide biochemical and functional evidence that PTEN/MMAC1 acts a negative regulator of the phosphoinositide 3-kinase (PI3-kinase)/Akt pathway. PTEN/MMAC1 impairs activation of endogenous Akt in cells and inhibits phosphorylation of 4E-BP1, a downstream target of the PI3-kinase/Akt pathway involved in protein translation, whereas a catalytically inactive, dominant negative PTEN/MMAC1 mutant enhances 4E-BP1 phosphorylation. In addition, PTEN/MMAC1 represses gene expression in a manner that is rescued by Akt but not PIS-kinase. Finally, higher levels of Akt activation are observed in human prostate cancer cell lines and xenografts lacking PTEN/MMAC1 expression when compared with PTEN/MMAC1-positive prostate tumors or normal prostate tissue. Because constitutive activation of either PI3-kinase or Akt is known to induce cellular transformation, an increase in the activation of this pathway caused by mutations in PTEN/MMAC1 provides a potential mechanism for its tumor suppressor function.