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 W ，Yu F ，Yan M ，Lu L ，Zou W ，Sun L ，Zheng Z ，Liu X ... -  《JOURNAL OF CELLULAR PHYSIOLOGY》

The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation.

Schnaider T ，Somogyi J ，Csermely P ，Szamel M ... -  《-》

Geldanamycin induces heat shock protein expression through activation of HSF1 in K562 erythroleukemic cells.

Kim HR ，Kang HS ，Kim HD 《IUBMB LIFE》

Geldanamycin interferes with the 90-kDa heat shock protein, affecting lipopolysaccharide-mediated interleukin-1 expression and apoptosis within macrophages.

Hsu HY ，Wu HL ，Tan SK ，Li VP ，Wang WT ，Hsu J ，Cheng CH ... -  《MOLECULAR PHARMACOLOGY》

Human leukemias with mutated FLT3 kinase are synergistically sensitive to FLT3 and Hsp90 inhibitors: the key role of the STAT5 signal transduction pathway.

Yao Q ，Nishiuchi R ，Kitamura T ，Kersey JH ... -  《LEUKEMIA》