Regulation of aryl hydrocarbon receptor signal transduction by protein tyrosine kinases

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• 作者：Backlund ; Maria ; Ingelman-Sundberg ; Magnus
• 关键词：AhR ; Omeprazole ; Protein tyrosine kinase ; c-src kinase ; Tyrphostin ; AhR ; aryl hydrocarbon receptor ; TCDD ; 2 ; 3 ; 7 ; 8-tetrachlorodibenzo-p-dioxin ; PAS ; Per-Arnt-Sim ; bHLH ; basic helix&ndash ; loop-helix ; hsp90 ; heat shock protein 90 ; arnt ; AhR nuclear transloca
• 刊名：Cellular Signalling
• 出版年：2005
• 出版时间：January, 2005
• 年：2005
• 卷：17
• 期：1
• 页码：39-48
• 全文大小：467 K

文摘

The involvement of protein tyrosine kinases (PTKs) in aryl hydrocarbon receptor (AhR)-mediated signalling by omeprazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated in hepatoma cells. Both omeprazole- and TCDD-dependent AhR signalling was attenuated by inhibition of c-src kinase, either by using pyrazolopyrimidine 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4 ]pyrimidine (PP1) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) inhibitors or by expression of dominant-negative c-src. These results indicate that the overall AhR function is modulated by c-src kinase activity. In contrast, a selective inhibition of omeprazole-mediated AhR signalling was revealed by tyrosine kinase inhibitors, tyrphostins AG17 and AG879. Furthermore, omeprazole-dependent AhR activation was abolished by mutation of Tyr³²⁰ to Phe, suggesting that this residue is a putative phosphorylation site. TCDD-dependent AhR signalling was neither affected by tyrphostins nor by this mutation. Our results are consistent with activation of the AhR by omeprazole in a ligand-independent manner, via a signal transduction pathway that involves protein tyrosine kinases, and are different from the mechanism exerted by high-affinity ligands.