Geldanamycin, a heat shock protein 90-binding agent, disrupts Stat5 activation in IL-2-stimulated cells.
The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone in eukaryotic cells. Hsp90 plays a critical role in regulating signal transduction pathways that control cell proliferation since its chaperone function is restricted to a subset of proteins including some signal molecules. Improper function of these proteins can be induced by an anti-tumor agent geldanamycin (GA) which is the specific inhibitor of Hsp90. In this study, it was demonstrated that GA interferes with IL-2-stimulated proliferation of murine CTLL-2 cells. As to the signaling mechanisms underlying this inhibitory effect, we discovered GA disrupts the IL-2-stimulated activation and phosphorylation of the transcription factor Stat5, indicating the proper function of Hsp90 is indispensable for Stat5 activation. This conclusion is validated by the observation that Hsp90 interacts with Stat5 in the immunoprecipitation assay and GA interrupts their interaction. Furthermore, by constructing deletion mutants, we identified the c-terminal half of Stat5 coiled-coil region is responsible for binding with Hsp90.
Xu
Weijing
W
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 YueYang Road, Shanghai, China.
Yu
Furong
F
Yan
Mingda
M
Lu
Linrong
L
Zou
Weiguo
W
Sun
Lanying
L
Zheng
Zhongcheng
Z
Liu
Xinyuan
X
D000818:Animals; D016227:Benzoquinones; D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D007376:Interleukin-2 / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008894:Milk Proteins; D009154:Mutation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011809:Quinones / Q000494:pharmacology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D008894:Milk Proteins; D011809:Quinones; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C001277:geldanamycin