Geldanamycin inhibits TGF-β signaling through induction of Hsp70

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Title
Geldanamycin inhibits TGF-β signaling through induction of Hsp70
Author(s)
C H Yun; S Y Yoon; T T Nguyen; H Y Cho; T H Kim; S T Kim; B C Kim; Young-Soo Hong; S J Kim; H J Lee
Bibliographic Citation
Archives of Biochemistry and Biophysics, vol. 495, no. 1, pp. 8-13
Publication Year
2010
Abstract
Dysregulation of transforming growth factor-β (TGF-β) signaling has been implicated in the pathogenesis of a variety of diseases including cancer; therefore, pharmacological inhibitors that target the TGF-β signaling pathway might be promising drugs for disease therapy. In this study, we investigated the mechanism of inhibition of TGF-β signaling by the Hsp90 inhibitor geldanamycin (GA). Treatment with GA suppressed TGF-β signaling, as evidenced by inhibition of TGF-β-induced phosphorylation and transcriptional activity of Smad3 and decreased induction of target genes. Western blot analysis revealed that GA induced degradation of TGF-β type I and type II receptors through a proteasome-dependent pathway. Notably, induction of Hsp70 by GA correlated with inhibition of TGF-β signaling. Suppression of Hsp70 expression by Hsp70 siRNA or KNK437, an inhibitor of Hsp70 synthesis, blocked the inhibition of TGF-β signaling by GA. Furthermore, Hsp70 interacted directly with TGF-β receptors following GA treatment. Our results suggest that GA-mediated induction of Hsp70 and its subsequent interaction with TGF-β receptors plays a crucial role in inhibition of TGF-β signaling.
Keyword
GeldanamycinHsp70Hsp90Receptor degradationTGF-β signaling
ISSN
0096-9621
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.abb.2009.12.003
Type
Article
Appears in Collections:
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
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