Title

Role of p38 mitogen-activated protein kinase in stress

Date of Completion

January 1999

Keywords

Biology, Molecular|Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

During its lifetime the cell has to respond to various stressful stimuli, to which it can adapt or undergo cell death. The stress signals perceived by the cell are relayed intracellularly via kinases. p38 MAP kinase is a major component of this stress activated cascade and hence plays a major role in determining the outcome. Studies have shown that it is involved in both, adaptive responses and apoptosis. The current study focuses on the role of p38 MAP kinase in two different stress situations—preconditioning and ischemia. Using rat myoblast cell fine H9C2 and in-vitro model of metabolically induced ischemia we found that p38 MAP kinase is activated by both, preconditioning stimuli and by lethal ischemic insult. Paradoxically, it plays a protective role in preconditioning and a deleterious role in lethal insult. In preconditioning, we found that p38 MAP kinase is activated, and phosphorylates small heat shock protein HSP 25. This leads to uncapping of F-actin and polymerization of G-actin to F-actin. We propose that it is the stabilization of actin filaments during the recovery, which enables it to withstand the second insult. On the other hand during lethal ischemia, the uncapping of F-actin in presence of continuous stress leads to depolymerization and destabilization of F-actin, which contributes to the deleterious effects. The duration of activation and the surrounding mileu during its activation determine whether the activation of p38 MAP kinase in stress has a protective or harmful effect. ^