Essential Role of AKT-1/Protein Kinase Bα in PTEN-Controlled Tumorigenesis

Stiles, Bangyan L.; Gilman, Valeriya; Khanzenzon, Natalya; Lesche, Ralf; Li, Annie; Qiao, Rong; Liu, Xin; Wu, Hong

doi:10.1128/mcb.22.11.3842-3851.2002

Cited by 135 publications

(91 citation statements)

References 37 publications

(52 reference statements)

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“…In C-elegans, the PTEN homolog, DAF-18, acts in insulin receptor-like pathway and regulates longevity and dauer larva development (12)(13)(14)(15). Hyperactivation of the PI3-kinase͞AKT pathway also appears to be a main result of Pten deletion in mammalian systems (16). Unfortunately, Pten-deficient mice die at early stage of embryonic development (17)(18)(19)(20), which precludes study of the role of PTEN in the mammalian insulin signaling pathway in a wholeanimal setting.…”

Section: Liver-specific Deletion Of Negative Regulator Pten Results Imentioning

confidence: 99%

Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

Stiles

Wang²,

Stahl³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes

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Section: Liver-specific Deletion Of Negative Regulator Pten Results Imentioning

confidence: 99%

Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

Stiles

Wang²,

Stahl³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

386

405

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show abstract

“…Loss of PTEN leads to higher activity of AKT, which modulates activities of multiple downstream factors via phosphorylation (Stiles et al, 2002). AKT phosphorylates and inhibits GSK3b activity, thereby leading to the stabilization of b-catenin (Diehl et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

Huang

et al. 2006

Oncogene

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PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3b and b-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3b, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3b/b-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.

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“…Prostate cancer cell lines LNCaP (27), PC-3 (28) and DU145 (29), and breast cancer line (33) and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) ϩ͞Ϫ mice (34,35). Hong Wu (UCLA) and Norman Greenberg (Baylor College of Medicine) kindly provided PTENϩ͞Ϫ and TRAMP mice, respectively.…”

Section: Methodsmentioning

confidence: 99%