Involvement of heat-shock protein 90 in the interleukin-6-mediated signaling pathway through STAT3.
Interleukin-6 (IL-6) is a multifunctional cytokine playing roles in the immune system, hematopoiesis, and acute phase reactions. IL-6 also regulates the growth of various types of human malignant tumors. Here we demonstrate that IL-6-induced gene expression was suppressed by a specific heat-shock protein 90 (Hsp90) inhibitor, geldanamycin (GA) in human ... hepatoma Hep3B cells. GA also suppressed the IL-6-induced activation of signal transducer and activator of transcription 3 (STAT3) in a human embryonic kidney carcinoma 293T cells. This inhibitory effect of GA on STAT3 activation was reversed by overexpression of Hsp90. Furthermore, Hsp90 directly bound to STAT3 via its N-terminal region, which interacted with GA. We provide evidence that the action of GA on IL-6 functions was due to the inhibition of direct physical interactions between STAT3 and Hsp90, which represents a novel role of Hsp90 in the IL-6 signaling pathways.
Mesh Terms:
Benzoquinones, Cysteine Proteinase Inhibitors, DNA-Binding Proteins, Gene Expression Regulation, Genes, Reporter, HSP90 Heat-Shock Proteins, Humans, Interleukin-6, Lactams, Macrocyclic, Quinones, Recombinant Proteins, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Tumor Cells, Cultured
Benzoquinones, Cysteine Proteinase Inhibitors, DNA-Binding Proteins, Gene Expression Regulation, Genes, Reporter, HSP90 Heat-Shock Proteins, Humans, Interleukin-6, Lactams, Macrocyclic, Quinones, Recombinant Proteins, STAT3 Transcription Factor, Signal Transduction, Trans-Activators, Tumor Cells, Cultured
Biochem. Biophys. Res. Commun.
Date: Jan. 24, 2003
PubMed ID: 12559950
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