Article (Scientific journals)
Geldanamycin inhibits tyrosine phosphorylation-dependent NF-kB activation
Crèvecoeur, Julie; Piette, Jacques; Gloire, Geoffrey
2008In Biochemical Pharmacology, 75 (11), p. 2183-2191
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Keywords :
Geldanamycin; NF-KappaB; Tyrosine phophorylation
Abstract :
[en] Hsp90 is a protein chaperone regulating the stability and activity of many signalling molecules. The requirement of Hsp90 activity in the NF-κB pathway has been recently reported by several authors using the Hsp90 ATPase inhibitor Geldanamycin (GA), an anti-tumour drug. Hsp90 inhibition blocks the synthesis and activation of the IKK complex, the major kinases complex responsible for IκBα phosphorylation on serine 32 and 36, a key step for its degradation and the nuclear translocation of NF-κB. However, the effect of GA on other IκBα kinases, including tyrosine kinases, is unknown. In the present study, we investigated the effect of GA on NF-κB activation induced by sodium pervanadate (PV), a tyrosine phosphatase inhibitor triggering c-Src-mediated tyrosine phosphorylation of IκBα. We reporte for the first time that GA inhibits PV-induced IκBα tyrosine phosphorylation and degradation. Using an in vitro kinase assay, we demonstrated that GA inhibits the activity of c-Src as an IκBα tyrosine kinase, but not its cellular expression. As a result, GA blocked PV-induced NF-κB DNA binding activity on an exogenous κB element and on the endogenous iκbα promoter, thereby inhibiting IκBα transcription. Finally, we demonstrated that, despite NF-κB inhibition, pre-treatment with GA does not potentiate PV-induced apoptosis. We conclude that c-Src requires Hsp90 for its tyrosine kinase activity, and its inhibition by GA blocks c-Src-dependent signalling pathways, such as NF-κB activation induced by sodium pervanadate. The effect of GA on PV-induced apoptosis is discussed in the light of recent publications in the literature.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Crèvecoeur, Julie ;  Université de Liège - ULiège > Département des sciences cliniques > Neuropathologie
Piette, Jacques ;  Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie - Département des sciences de la vie - GIGA-Research
Gloire, Geoffrey ;  Université de Liège - ULiège > GIGA-R : Virologie - Immunologie
Language :
English
Title :
Geldanamycin inhibits tyrosine phosphorylation-dependent NF-kB activation
Publication date :
2008
Journal title :
Biochemical Pharmacology
ISSN :
0006-2952
eISSN :
1873-2968
Publisher :
Elsevier Science, Oxford, United Kingdom
Volume :
75
Issue :
11
Pages :
2183-2191
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 23 December 2009

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