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  • The EMBO Journal (1999) 18, 1321 - 1334
  • doi:10.1093/emboj/18.5.1321

Regulation of JNK signaling by GSTp

Victor Adler1, Zhimin Yin1, Serge Y. Fuchs1, Miriam Benezra1, Lilliam Rosario2, Kenneth D. Tew2, Matthew R. Pincus3, Mohinder Sardana4, Colin J. Henderson5, C.Roland Wolf5, Roger J. Davis6 and Ze'ev Ronai1

  1. The Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L.Levy Place, Box 1130, New York, NY 10029-6574, USA
  2. Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA, USA
  3. Department of Pathology and Laboratory Medicine, SUNY Health Science Center, Brooklyn, NY, USA
  4. Protein Sequencing Facility, Merck Sharp & Dohme, West Point, PA, USA
  5. Imperial Cancer Research Fund, Molecular Pharmacology Unit, Dundee, DD1 9SY, UK
  6. Howard Hughes Medical Institute, University of Massachusetts, Worcester, MA, USA

Correspondence to:

Ze'ev Ronai, E-mail: ronaiz01@doc.mssm.edu

Received 19 November 1998; Accepted 8 January 1999; Revised 8 January 1999

Studies of low basal Jun N-terminal kinase (JNK) activity in non-stressed cells led us to identify a JNK inhibitor that was purified and identified as glutathione S-transferase Pi (GSTp) and was characterized as a JNK-associated protein. UV irradiation or H2O2 treatment caused GSTp oligomerization and dissociation of the GSTp–JNK complex, indicating that it is the monomeric form of GSTp that elicits JNK inhibition. Addition of purified GSTp to the Jun–JNK complex caused a dose-dependent inhibition of JNK activity. Conversely, immunodepleting GSTp from protein extracts attenuated JNK inhibition. Furthermore, JNK activity was increased in the presence of specific GSTp inhibitors and a GSTp-derived peptide. Forced expression of GSTp decreased MKK4 and JNK phosphorylation which coincided with decreased JNK activity, increased c-Jun ubiquitination and decreased c-Jun-mediated transcription. Co-transfection of MEKK1 and GSTp restored MKK4 phosphorylation but did not affect GSTp inhibition of JNK activity, suggesting that the effect of GSTp on JNK is independent of the MEKK1–MKK4 module. Mouse embryo fibroblasts from GSTp-null mice exhibited a high basal level of JNK activity that could be reduced by forced expression of GSTp cDNA. In demonstrating the relationships between GSTp expression and its association with JNK, our findings provide new insight into the regulation of stress kinases.

  • Keywords:

    • GSTp,
    • JNK,
    • signaling,
    • stress kinase