Essential role of AKT-1/protein kinase Bα in PTEN-controlled tumorigenesis

被引:118
作者
Stiles, B
Gilman, V
Khanzenzon, N
Lesche, R
Li, A
Qiao, R
Liu, X
Wu, H
机构
[1] Univ Calif Los Angeles, Sch Med, Howard Hughes Med Inst, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA
关键词
D O I
10.1128/MCB.22.11.3842-3851.2002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
PTEN is mutated at high frequency in many primary human cancers and several familial cancer predisposition disorders. Activation of AKT is a common event in tumors in which the PTEN gene has been inactivated. We previously showed that deletion of the murine Pten gene in embryonic stem (ES) cells led to increased phosphatidylinositol triphosphate (PIP3) accumulation, enhanced entry into S phase, and better cell survival. Since PIP3 controls multiple signaling molecules, it was not clear to what degree the observed phenotypes were due to deregulated AKT activity. In this study, we mutated Akt-1 in Pten(-/-) ES cells to directly assess the role of AKT-1 in PTEN-controlled cellular processes, such as cell proliferation, cell survival, and tumorigenesis in nude mice. We showed that AKT-1 is one of the major downstream effectors of PTEN in ES cells and that activation of AKT-1 is required for both the cell survival and cell proliferation phenotypes observed in Pten(-/-) ES cells. Deletion of Akt-1 partially reverses the aggressive growth of Pten(-/-) ES cells in vivo, suggesting that AKT-1 plays an essential role in PTEN-controlled tumorigenesis.
引用
收藏
页码:3842 / 3851
页数:10
相关论文
共 40 条
[1]   Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase [J].
Ahmed, NN ;
Grimes, HL ;
Bellacosa, A ;
Chan, TO ;
Tsichlis, PN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (08) :3627-3632
[2]  
ALTOMARE DA, 1995, ONCOGENE, V11, P1055
[3]   Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B [J].
Anderson, KE ;
Coadwell, J ;
Stephens, LR ;
Hawkins, PT .
CURRENT BIOLOGY, 1998, 8 (12) :684-691
[4]  
ANDIELKOVIC M, 1997, J BIOL CHEM, V272, P31515
[5]   CHARACTERIZATION OF THE BREAKPOINT OF A T(14-14)(Q11.2-Q32) FROM THE LEUKEMIC-CELLS OF A PATIENT WITH T-CELL ACUTE LYMPHOBLASTIC-LEUKEMIA [J].
BERTNESS, VL ;
FELIX, CA ;
MCBRIDE, OW ;
MORGAN, R ;
SMITH, SD ;
SANDBERG, AA ;
KIRSCH, IR .
CANCER GENETICS AND CYTOGENETICS, 1990, 44 (01) :47-54
[6]   Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F [J].
Brennan, P ;
Babbage, JW ;
Burgering, BMT ;
Groner, B ;
Reif, K ;
Cantrell, DA .
IMMUNITY, 1997, 7 (05) :679-689
[7]   Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].
Brunet, A ;
Bonni, A ;
Zigmond, MJ ;
Lin, MZ ;
Juo, P ;
Hu, LS ;
Anderson, MJ ;
Arden, KC ;
Blenis, J ;
Greenberg, ME .
CELL, 1999, 96 (06) :857-868
[8]   Regulation of cell death protease caspase-9 by phosphorylation [J].
Cardone, MH ;
Roy, N ;
Stennicke, HR ;
Salvesen, GS ;
Franke, TF ;
Stanbridge, E ;
Frisch, S ;
Reed, JC .
SCIENCE, 1998, 282 (5392) :1318-1321
[9]   AKT2, A PUTATIVE ONCOGENE ENCODING A MEMBER OF A SUBFAMILY OF PROTEIN-SERINE THREONINE KINASES, IS AMPLIFIED IN HUMAN OVARIAN CARCINOMAS [J].
CHENG, JQ ;
GODWIN, AK ;
BELLACOSA, A ;
TAGUCHI, T ;
FRANKE, TF ;
HAMILTON, TC ;
TSICHLIS, PN ;
TESTA, JR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (19) :9267-9271
[10]  
Coffer PJ, 1998, BIOCHEM J, V335, P1