The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling.
The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling.
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磷酸肌醇3-激酶调节亚基P85Alpha可以通过阴性调节生长因子信号传导来发挥肿瘤抑制特性。
DOI：
10.1158/0008-5472.can-09-3399
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发表时间：
2010-07-01
期刊：
影响因子：
11.2
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Taniguchi CM;Winnay J;Kondo T;Bronson RT;Guimaraes AR;Alemán JO;Luo J;Stephanopoulos G;Weissleder R;Cantley LC;Kahn CR
PI 3 K在肿瘤发生中起着关键作用，PI 3 K p85调节亚基对信号传导发挥积极和消极的作用。Pik 3r 1，编码p85的基因，在人前列腺癌、肺癌、卵巢癌、膀胱癌和肝癌中的表达降低，这与p85具有肿瘤抑制特性的可能性一致。我们通过研究肝脏特异性缺失Pik 3r 1基因的小鼠来验证这一假设。这些小鼠表现出增强的胰岛素和生长因子信号传导以及肝脏病理学的进行性变化，导致发生侵袭性肝细胞癌伴肺转移。出现的肝肿瘤在mRNA和蛋白质水平上表现出显著升高的磷脂酰肌醇-3，4，5-三磷酸（PIP 3）水平，沿着Akt活化和降低的PTEN表达。总之，这些结果证实了PI 3 K的p85亚基在肝脏和可能的其他组织中具有肿瘤抑制作用的概念。
PI3K plays a critical role in tumorigenesis and the PI3K p85 regulatory subunit exerts both positive and negative effects on signaling. Expression of Pik3r1, the gene encoding p85, is decreased in human prostate, lung, ovarian, bladder and liver cancers consistent with the possibility that p85 has tumor suppressor properties. We tested this hypothesis by studying mice with a liver-specific deletion of the Pik3r1 gene. These mice exhibited enhanced insulin and growth factor signaling and progressive changes in hepatic pathology, leading to the development of aggressive hepatocellular carcinomas with pulmonary metastases. Liver tumors that arose exhibited a markedly elevated level of phosphatidylinositol-3,4,5-trisphosphate (PIP3), along with Akt activation and and decreased PTEN expression, at both the mRNA and protein levels. Together, these results substantiate the concept that the p85 subunit of PI3K has a tumor suppressive role in the liver and possibly other tissues.