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Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2–ASK1 signals

Oncogene volume 25, pages 5787–5800 (2006)Cite this article

Abstract

Human glutathione S-transferase P1-1 (GSTP1-1) is an ubiquitously expressed protein that plays an important role in the detoxification and xenobiotics metabolism. It has been shown that GSTP1-1 interacts with c-Jun NH2-terminal kinase (JNK) and suppresses its activity. Here, we report a novel function of GSTP1-1 in regulating tumor necrosis factor-α (TNF-α)-triggered signaling. The present experiments showed that GSTP1-1 physically associated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in vivo and in vitro. Overexpression of GSTP1-1 inhibited TRAF2-induced activation of both JNK and p38 but not of nuclear factor-κB (NF-κB). Glutathione S-transferase P1-1 also attenuated TRAF2-enhanced apoptosis signal-regulating kinase 1 (ASK1) autophosphorylation and inhibited TRAF2–ASK1-induced cell apoptosis by suppressing the interaction of TRAF2 and ASK1. Conversely, silencing of GSTP1-1 expression through RNA interference (RNAi) resulted in increase of TNF-α-dependent TRAF2–ASK1 association followed by hyper-activation of ASK1 and JNK. A mutant GSTP1-1 lacking TRAF domain-binding motif exhibited a significant decline of capacity to bind TRAF2 and block TRAF2–ASK1 signaling compared with the wild type of GSTP1-1. Moreover, the glutathione-conjugating activity of GSTP1-1 was not involved in the regulation of TRAF2 signaling. These findings indicate that GSTP1-1 plays an important regulatory role in TNF-α-induced signaling by forming ligand-binding interactions with TRAF2, which provides a new insight for analysing the protective effects of GSTP1-1 in tumor cells.

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Acknowledgements

We particularly thank Dr Ze'ev Ronai and Dr Zhenguo Wu for providing partial constructs used in this study, we also thank Huaqun Chen for technical assistance. This work was supported by grants from the Major State Basic Research Development Program of China (No. 2002CB513000) and National Nature Science Foundation of China (No. 30270527).

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Authors and Affiliations

  1. Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, JiangSu, People's Republic of China

    Y Wu, Y Fan, J Shen, S Zhang & Z Yin

  2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China

    B Xue & L Luo

  3. Department of Pathophysiology, Key Laboratory of Functional Proteomics of Guangdong Province, Southern Medical University, Guangzhou, People's Republic of China

    Y Jiang

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  1. Y Wu
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Correspondence to Z Yin.

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Wu, Y., Fan, Y., Xue, B. et al. Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2–ASK1 signals. Oncogene 25, 5787–5800 (2006). https://doi.org/10.1038/sj.onc.1209576

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