Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN+/- mice

Jose R. Bayascas, Nick R. Leslie, Ramon Parsons, Stewart Fleming, Dario R. Alessi

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Many cancers possess elevated levels of PtdIns(3,4,5)P3, the second messenger that induces activation of the protein kinases PKB/Akt and S6K and thereby stimulates cell proliferation, growth, and survival [1, 2]. The importance of this pathway in tumorigenesis has been highlighted by the finding that PTEN, the lipid phosphatase that breaks down PtdIns(3,4,5)P3 to PtdIns(4,5)P2, is frequently mutated in human cancer [3, 4].Cells lacking PTEN possess elevated levels of PtdIns(3,4,5)P3, PKB, and S6K activity [5-8] and heterozygous PTEN+/- mice develop a variety of tumors [9-11]. Knockout of PKBα in PTEN-deficient cells reduces aggressive growth and promotes apoptosis [12], whereas treatment of PTEN+/- mice with rapamycin, an inhibitor of the activation of S6K, reduces neoplasia [13]. We explored the importance of PDK1, the protein kinase that activates PKB and S6K [14], in mediating tumorigenesis caused by the deletion of PTEN. We demonstrate that reducing the expression of PDK1 in PTEN+/- mice, markedly protects these animals from developing a wide range of tumors. Our findings provide genetic evidence that PDK1 is a key effector in mediating neoplasia resulting from loss of PTEN and also validate PDK1 as a promising anticancer target for the prevention of tumors that possess elevated PKB and S6K activity.

Original languageEnglish
Pages (from-to)1839-1846
Number of pages8
JournalCurrent Biology
Volume15
Issue number20
DOIs
StatePublished - 25 Oct 2005
Externally publishedYes

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