New Insights into the Mechanism of JNK1 Inhibition by Glutathione Transferase P1-1

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• 作者：Anastasia De Luca ; Luca Federici ; Michele De Canio ; Lorenzo Stella ; Anna Maria Caccuri
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：September 18, 2012
• 年：2012
• 卷：51
• 期：37
• 页码：7304-7312
• 全文大小：427K
• 年卷期：v.51,no.37(September 18, 2012)
• ISSN：1520-4995

文摘

The role played by glutathione transferase P1-1 (GSTP1-1) in modulating the c-Jun N-terminal kinase (JNK) pathway has been extensively investigated using JNK isoforms known to exert opposite effects in the cells. We have expressed isoform JNK1伪2, which has been reported to transmit a pro-apoptotic signal, and we have analyzed both the phosphorylation level and the activity of this kinase in the presence of GSTP1-1. Contrary to what previous studies suggest, we found that GSTP1-1 is able to form a complex with the unphosphorylated and inactive JNK1伪2 isoform, even in the absence of the substrate. We also analyzed the consequences of this interaction on the activity of both enzymes. The complex strongly reduced the extent of activation of JNK1伪2 and preserved GSTP1-1 from inactivation. Unexpectedly, glutathione (GSH) exerted a negative effect on the affinity of GSTP1-1 for JNK1伪2, suggesting that the intracellular levels of this thiol may allow a fine-tuning of the MAPK signaling pathway. Moreover, we found that the adduct formed by GSH and the strong GSTP1-1 inhibitor NBDHEX abolishes the interaction between GSTP1-1 and JNK1伪2. These data confirm and extend at the molecular level previous evidence obtained in tumor cell lines.