TY - JOUR
T1 - The phosphoinositide 3-kinase regulatory subunit p85α can exert tumor suppressor properties through negative regulation of growth factor signaling
AU - Taniguchi, Cullen M.
AU - Winnay, Jonathon
AU - Kondo, Tatsuya
AU - Bronson, Roderick T.
AU - Guimaraes, Alexander R.
AU - Alemán, José O.
AU - Luo, Ji
AU - Stephanopoulos, Gregory
AU - Weissleder, Ralph
AU - Cantley, Lewis C.
AU - Kahn, C. Ronald
PY - 2010/7/1
Y1 - 2010/7/1
N2 - Phosphoinositide 3-kinase (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 liverspecific 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 markedly elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, along with Akt activation 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.
AB - Phosphoinositide 3-kinase (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 liverspecific 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 markedly elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, along with Akt activation 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.
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U2 - 10.1158/0008-5472.CAN-09-3399
DO - 10.1158/0008-5472.CAN-09-3399
M3 - Article
C2 - 20530665
AN - SCOPUS:77954367305
SN - 0008-5472
VL - 70
SP - 5305
EP - 5315
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -