Geldanamycin, an inhibitor of the chaperone activity of hsp90, induces mapk-independent cell cycle arrest

被引:44
作者
Bedin, M [1 ]
Gaben, AM [1 ]
Saucier, C [1 ]
Mester, J [1 ]
机构
[1] Hop St Antoine, INSERM U482, F-75571 Paris, France
关键词
D O I
10.1002/ijc.20010
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The effects of GA, an ansamycin antibiotic in development as a lead anticancer drug, were studied in mouse BP-A31 fibroblasts and in human cancer-derived cell lines. GA and related molecules act by inhibiting the chaperone function of the Hsp90 protein through competition for ATP binding. The antiproliferative effects of GA have been attributed to destabilization of the Raf-I protein, one of the targets of Hsp90, and to the resulting inhibition of MAPK. Addition of GA to BP-A31 cells, synchronously progressing through the G, phase, inhibited Rb hyperphosphorylation and G(1)/S transition irrespective of the time of addition. The G I arrest was accompanied by a progressive decrease in Raf-I content, especially of the phosphorylated form; however, GA caused only partial inhibition of MAPK phosphorylation. We show that GA triggers a rapid and marked decrease in the kinase activity of the cyclin E/cdk2 complex coupled with a decline in both total and cdk2-associated cyclin E. In transient transfection experiments, inhibition of cyclin E expression by GA was correlated with inhibition of the transcriptional activity of the cyclin E gene promoter. Inhibition of cdk4 activity by GA was observed 3 hr after addition of the drug to late G I cells but not after a short (I hr) exposure, as revealed by the phosphorylation of Rb on the Ser(780) residue. In human cancer-derived cell lines expressing or not a functional Rb protein, GA blocked proliferation and inhibited the transcriptional activity of the cyclin E gene promoter. In these cell lines, the antiproliferative effect of GA was not limited to the G, phase, suggesting the existence of multiple cellular targets of the drug. (C) 2004 Wiley-Liss, Inc.
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页码:643 / 652
页数:10
相关论文
共 59 条
[1]  
Ahn Natalie G., 1992, Current Opinion in Cell Biology, V4, P992, DOI 10.1016/0955-0674(92)90131-U
[2]   Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27(KIP1) [J].
Aktas, H ;
Cai, H ;
Cooper, GM .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (07) :3850-3857
[3]   The cyclin-dependent kinase inhibitors olomoucine and roscovitine arrest human fibroblasts in G1 phase by specific inhibition of CDK2 kinase activity [J].
Alessi, F ;
Quarta, S ;
Savio, M ;
Riva, F ;
Rossi, L ;
Stivala, LA ;
Scovassi, AI ;
Meijer, L ;
Prosperi, E .
EXPERIMENTAL CELL RESEARCH, 1998, 245 (01) :8-18
[4]   Cdk2-dependent and -independent pathways in E2F-mediated S phase induction [J].
Arata, Y ;
Fujita, M ;
Ohtani, K ;
Kijima, S ;
Kato, JY .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (09) :6337-6345
[5]   RAF MEETS RAS - COMPLETING THE FRAMEWORK OF A SIGNAL-TRANSDUCTION PATHWAY [J].
AVRUCH, J ;
ZHANG, XF ;
KYRIAKIS, JM .
TRENDS IN BIOCHEMICAL SCIENCES, 1994, 19 (07) :279-283
[6]  
Botz J, 1996, MOL CELL BIOL, V16, P3401
[7]   Hsp90 & Co. - a holding for folding [J].
Buchner, J .
TRENDS IN BIOCHEMICAL SCIENCES, 1999, 24 (04) :136-141
[8]   MITOGENIC ACTIVITY OF PHORBOL ESTERS AND INSULIN-LIKE GROWTH FACTOR-I IN CHEMICALLY TRANSFORMED MOUSE FIBROBLASTS BP-A31 - INDEPENDENT EFFECTS AND DIFFERENTIAL SENSITIVITY TO INHIBITION BY 3-ISOBUTYL-1-METHYL XANTHINE [J].
BUCHOU, T ;
CHAROLLAIS, RH ;
FAGOT, D ;
MESTER, J .
EXPERIMENTAL CELL RESEARCH, 1989, 182 (01) :129-143
[9]   FIBROBLAST GROWTH FACTOR-DEPENDENT MITOGENIC SIGNAL TRANSDUCTION PATHWAY IN CHEMICALLY TRANSFORMED MOUSE FIBROBLASTS IS SIMILAR TO BUT DISTINCT FROM THAT INITIATED BY PHORBOL ESTERS [J].
BUCHOU, T ;
MESTER, J .
JOURNAL OF CELLULAR PHYSIOLOGY, 1990, 142 (03) :559-565
[10]  
BuquetFagot C, 1996, J CELL PHYSIOL, V166, P631, DOI 10.1002/(SICI)1097-4652(199603)166:3<631::AID-JCP18>3.0.CO