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 journalArticle

127 Citations (Scopus)

Abstract

Many cancers possess elevated levels of PtdIns(3,4,5)P(3), the second messenger that induces activation of the protein kinases PKB/Akt and S6K and thereby stimulates cell proliferation, growth, and survival. 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)P(3) to PtdIns(4,5)P(2), is frequently mutated in human cancer. Cells lacking PTEN possess elevated levels of PtdIns(3,4,5)P(3), PKB, and S6K activity and heterozygous PTEN(+/-) mice develop a variety of tumors. Knockout of PKBalpha in PTEN-deficient cells reduces aggressive growth and promotes apoptosis, whereas treatment of PTEN(+/-) mice with rapamycin, an inhibitor of the activation of S6K, reduces neoplasia. We explored the importance of PDK1, the protein kinase that activates PKB and S6K, 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
Publication statusPublished - 25 Oct 2005

Keywords

  • Age Factors
  • Animals
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Neoplasms
  • PTEN Phosphohydrolase
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • Survival Analysis

Fingerprint Dive into the research topics of 'Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice'. Together they form a unique fingerprint.

  • Cite this