TY - JOUR
T1 - Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN+/- mice
AU - Bayascas, Jose R.
AU - Leslie, Nick R.
AU - Parsons, Ramon
AU - Fleming, Stewart
AU - Alessi, Dario R.
N1 - Funding Information:
We thank the Tissue Bank of the University of Dundee for histological preparation and George Thompson for help with immunohistochemistry analysis, Leah Ronaldson and Gail Fraser for assistance with genotyping of mice and the antibody purification team (Division of Signal Transduction Therapy, University of Dundee) coordinated by Hilary McLauchlan and James Hastie for generation and purification of antibodies. A long-term fellowship from EMBO as well as a Marie Curie Fellowship supported J.R.B. We thank the Philip Leverhulme Trust Prize as well as the Association for International Cancer Research (D.R.A.), Diabetes UK (D.R.A.) the Medical Research Council (D.R.A.), the Moffat Charitable Trust (D.R.A.), and the pharmaceutical companies supporting the Division of Signal Transduction Therapy (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck & Co., Inc, Merck KGaA, and Pfizer) for financial support.
PY - 2005/10/25
Y1 - 2005/10/25
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/27144480288
U2 - 10.1016/j.cub.2005.08.066
DO - 10.1016/j.cub.2005.08.066
M3 - Article
C2 - 16243031
AN - SCOPUS:27144480288
SN - 0960-9822
VL - 15
SP - 1839
EP - 1846
JO - Current Biology
JF - Current Biology
IS - 20
ER -