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

TY - JOUR

T1 - Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice

AU - Bayascas, Jose R.

AU - Leslie, Nicholas

AU - Parsons, Ramon

AU - Fleming, Stewart

AU - Alessi, Dario

N1 - dc.publisher: Elsevier (Cell Press)

PY - 2005/10

Y1 - 2005/10

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] 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.

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] 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.

U2 - 10.1016/j.cub.2005.08.066

DO - 10.1016/j.cub.2005.08.066

M3 - Article

C2 - 16243031

SN - 0960-9822

VL - 15

SP - 1839

EP - 1846

JO - Current Biology

JF - Current Biology

IS - 20

ER -