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Heat shock-induced signal transduction in hematopoietic cells Gerl, Robert E.

Abstract

Heat shock is a cellular stress that induces a characteristic set of signalling events, many of which are highly conserved throughout evolution. This includes the increased synthesis of a set of protein chaperones known as heat shock proteins (hsps) which facilitates survival during harsh environmental conditions. In eukaryotes, heat shock also leads to the stimulation of signalling pathways that negatively regulate translation via phosphorylation of the eukaryotic initiation factor 2α and also activate protein kinases of the MAPK superfamily. In mammals, the JNK and p38 MAPK signalling cascades have been found to be activated in response to numerous forms of environmental stress, including heat shock, however the mechanisms governing their activation in response to these stresses are poorly understood. In this work, the activation status of the JNK signalling cascade was investigated in a variety of cell types following heat shock treatment. Surprisingly, we have found that the degree of JNK activation that occurs in response to heat shock varies markedly in different murine cell types. Thus, while heat shock induced strong activation in macrophages and mast cells, a dramatically reduced activation was noted in T and B lymphocytes. Despite the lack of heat-induced JNK activation in murine lymphocytes, they could respond to heat shock in terms of the induction of the heat shock protein response which includes phosphorylation of the heat shock factor 1 (HSF1) and subsequent upregulation of the heat shock protein, Hsp70. In addition, we found that heat shock in murine lymphocytes, as in other cells, led to the phosphorylation of the eukaryotic initiation factor 2α (elF2α). These findings suggest that JNK signalling may be dispensable for the activation of the heat shock protein response and translational inhibition mediated by elF2α. To help understand the mechanistic basis for the altered JNK signalling response in murine lymphocytes, the potential involvement of various proximal signalling events in the activation of JNK during heat shock was investigated. It was found that both of the JNK kinases, MKK4 and MKK7 were activated during heat shock in most cells although not in murine lymphocytes. We also discovered that, unlike all other cell types tested, murine lymphocytes failed to activate JNK in response to the ribosomal toxin anisomycin, suggesting that there may be a common mechanistic link between the effects of this compound and heat shock on JNK activation. To address the possible biological significance of attenuated JNK signalling in murine lymphocytes in response to heat shock, we compared the induction of apoptosis in these cells with non-lymphoid cells. These studies indicated that murine lymphoid cells were, in fact, more susceptible to undergoing apoptosis as compared to non-lymphoid cells during heat shock. Thus, our evidence suggests that JNK activation is not likely to be the main factor influencing the progression of apoptosis in cells exposed to heat shock. We speculate that the attenuation of JNK signalling in murine lymphocytes during heat shock is due to the possible negative influence of this pathway on aspects of lymphocyte function during this form of stress or others that mimic its effects.

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