Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice.
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.
Bayascas
Jose R
JR
MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom. j.bayascas@dundee.ac.uk
Leslie
Nick R
NR
Parsons
Ramon
R
Fleming
Stewart
S
Alessi
Dario R
DR
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000367:Age Factors; D000818:Animals; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis
D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse