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Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2002 Aug 23; Vol. 277 (34), pp. 30792-7. Date of Electronic Publication: 2002 Jun 19. - Publication Year :
- 2002
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Abstract
- Despite the importance of the stress-activated protein kinase pathways in cell death and survival, it is unclear how stressful stimuli lead to their activation. In the case of heat shock, the existence of a specific mechanism of activation has been evidenced, but the molecular nature of this pathway is undefined. Here, we found that Ask1 (apoptosis signal-regulating kinase 1), an upstream activator of the stress-activated protein kinase p38 during exposure to oxidative stress and other stressful stimuli, was also activated by heat shock. Ask1 activity was required for p38 activation since overexpression of a kinase dead mutant of Ask1, Ask1(K709M), inhibited heat shock-induced p38 activation. The activation of Ask1 by oxidative stress involves the oxidation of thioredoxin, an endogenous inhibitor of Ask1. A different activation mechanism takes place during heat shock. In contrast to p38 induction by H(2)O(2), induction by heat shock was not antagonized by pretreatment with the antioxidant N-acetyl-l-cysteine or by overexpressing thioredoxin and was not accompanied by the dissociation of thioredoxin from Ask1. Instead, heat shock caused the dissociation of glutathione S-transferase Mu1-1 (GSTM1-1) from Ask1 and overexpression of GSTM1-1-inhibited induction of p38 by heat shock. We concluded that because of an alternative regulation by the two distinct repressors thioredoxin and GSTM1-1, Ask1 constitutes the converging point of the heat shock and oxidative stress-sensing pathways that lead to p38 activation.
- Subjects :
- Animals
Cricetinae
Cricetulus
Enzyme Activation
Glutathione Transferase chemistry
HeLa Cells
Humans
Hydrogen Peroxide pharmacology
MAP Kinase Kinase Kinase 5
MAP Kinase Kinase Kinases chemistry
Thioredoxins pharmacology
p38 Mitogen-Activated Protein Kinases
Glutathione Transferase physiology
Hot Temperature
MAP Kinase Kinase Kinases physiology
Mitogen-Activated Protein Kinases physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 277
- Issue :
- 34
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12077134
- Full Text :
- https://doi.org/10.1074/jbc.M203642200