Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase Akt-dependent pathway

被引:443
作者
Muise-Helmericks, RC
Grimes, HL
Bellacosa, A
Malstrom, SE
Tsichlis, PN
Rosen, N
机构
[1] Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA
[3] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA
关键词
D O I
10.1074/jbc.273.45.29864
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
Cyclin D expression is regulated by growth factors and is necessary for the induction of mitogenesis. Herbimycin A, a drug that binds to Hsp90, induces the destruction of tyrosine kinases and causes the down-regulation of cyclin D and an Rb-dependent growth arrest in the G(1) phase of the cell cycle. We find that the induction of D cyclin expression by serum and its repression by herbimycin A are regulated at the level of mRNA translation. Induction of cyclin D by serum occurs prior to the induction of its mRNA and does not require transcription. Herbimycin A repression is characterized by a decrease in the synthetic rate of D-cyclins prior to changes in mRNA expression and in the absence of changes in the half-life of the protein, This effect on D-cyclin translation is mediated via a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. PI 3-kinase inhibitors such as wortmannin and LY294002, and rapamycin, an inhibitor of FRAP/TOR, cause a decline in the level of D-cyclins, whereas inhibitors of mitogen-activated protein kinase kinase and farnesyltransferase do not. Cells expressing the activated, myristoylated form of Akt kinase, a target of PI 3-kinase, are refractory to the effects of herbimycin A or serum starvation on D-cyclin expression. These data suggest that serum induction of cyclin D expression results from enhanced translation of its mRNA and that this results from activation of a pathway that is dependent upon PI 3-kinase and Akt kinase.
引用
收藏
页码:29864 / 29872
页数:9
相关论文
共 74 条
[31]   RAPAMYCIN SELECTIVELY REPRESSES TRANSLATION OF THE POLYPYRIMIDINE TRACT MESSENGER-RNA FAMILY [J].
JEFFERIES, HBJ ;
REINHARD, C ;
KOZMA, SC ;
THOMAS, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4441-4445
[32]  
JIANG W, 1993, ONCOGENE, V8, P3447
[33]   The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal [J].
Kennedy, SG ;
Wagner, AJ ;
Conzen, SD ;
Jordan, J ;
Bellacosa, A ;
Tsichlis, PN ;
Hay, N .
GENES & DEVELOPMENT, 1997, 11 (06) :701-713
[34]  
KIPPEL A, 1997, MOL CELL BIOL, V17, P338
[35]  
Klinghoffer RA, 1996, MOL CELL BIOL, V16, P5905
[36]   Construction and characterization of a conditionally active version of the serine/threonine kinase Akt [J].
Kohn, AD ;
Barthel, A ;
Kovacina, KS ;
Boge, A ;
Wallach, B ;
Summers, SA ;
Birnbaum, MJ ;
Scott, PH ;
Lawrence, JC ;
Roth, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (19) :11937-11943
[37]   Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt [J].
Kulik, G ;
Klippel, A ;
Weber, MJ .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (03) :1595-1606
[38]   RAPAMYCIN SELECTIVELY INHIBITS INTERLEUKIN-2 ACTIVATION OF P70 S6 KINASE [J].
KUO, CJ ;
CHUNG, JK ;
FIORENTINO, DF ;
FLANAGAN, WM ;
BLENIS, J ;
CRABTREE, GR .
NATURE, 1992, 358 (6381) :70-73
[39]   GROWTH FACTOR-INDUCED DELAYED EARLY RESPONSE GENES [J].
LANAHAN, A ;
WILLIAMS, JB ;
SANDERS, LK ;
NATHANS, D .
MOLECULAR AND CELLULAR BIOLOGY, 1992, 12 (09) :3919-3929
[40]   Cyclin D1 expression is regulated positively by the p42/p44(MAPK) and negatively by the p38/HOG(MAPK) pathway [J].
Lavoie, JN ;
LAllemain, G ;
Brunet, A ;
Muller, R ;
Pouyssegur, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (34) :20608-20616