Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1.
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.
Dorion
Sonia
S
Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, Quebec G1R 2J6, Canada.
Lambert
Herman
H
Landry
Jacques
J
D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000737:chemistry / Q000502:physiology*; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D013879:Thioredoxins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D005982:Glutathione Transferase; D006861:Hydrogen Peroxide; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D013879:Thioredoxins; D048051:p38 Mitogen-Activated Protein Kinases; C482858:MAP3K5 protein, human