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

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

    Research output: Contribution to journalArticlepeer-review

    134 Citations (Scopus)


    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] and [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] and [4]].Cells lacking PTEN possess elevated levels of PtdIns(3,4,5)P3, PKB, and S6K activity [[5], [6], [7] and [8]] and heterozygous PTEN+/- mice develop a variety of tumors [[9], [10] and [11]]. Knockout of PKBa 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
    Issue number20
    Publication statusPublished - Oct 2005


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