Geldanamycin inhibits TGF-beta signaling through induction of Hsp70.

Dysregulation of transforming growth factor-beta (TGF-beta) signaling has been implicated in the pathogenesis of a variety of diseases including cancer; therefore, pharmacological inhibitors that target the TGF-beta signaling pathway might be promising drugs for disease therapy. In this study, we investigated the mechanism of inhibition of TGF-beta signaling by the ...
Hsp90 inhibitor geldanamycin (GA). Treatment with GA suppressed TGF-beta signaling, as evidenced by inhibition of TGF-beta-induced phosphorylation and transcriptional activity of Smad3 and decreased induction of target genes. Western blot analysis revealed that GA induced degradation of TGF-beta type I and type II receptors through a proteasome-dependent pathway. Notably, induction of Hsp70 by GA correlated with inhibition of TGF-beta signaling. Suppression of Hsp70 expression by Hsp70 siRNA or KNK437, an inhibitor of Hsp70 synthesis, blocked the inhibition of TGF-beta signaling by GA. Furthermore, Hsp70 interacted directly with TGF-beta receptors following GA treatment. Our results suggest that GA-mediated induction of Hsp70 and its subsequent interaction with TGF-beta receptors plays a crucial role in inhibition of TGF-beta signaling.
Mesh Terms:
Benzoquinones, Cell Line, Gene Expression Regulation, HSP70 Heat-Shock Proteins, Humans, Lactams, Macrocyclic, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta, Ubiquitination
Arch. Biochem. Biophys.
Date: Mar. 01, 2010
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