RECONSTITUTION OF NOVEL SIGNALING CASCADES RESPONDING TO CELLULAR STRESSES

Mammalian cells respond to their immediate environment by inducing sig nal transduction cascades that regulate metabolism, secretion and gene expression. Several of these signalling pathways are structurally and organizationally related insofar as they require activation of a prot ein-serine kinase via it's phosphorylation on tyrosine and threonine; the archetype being mitogen-activated protein kinase (MAPK) which resp onds primarily to mitogenic stimuli via Ras. In contrast, two more rec ently identified cascades are responsive to cellular stresses such as heat, inflammatory cytokines, ischaemia and metabolic poisons. The rec ent identification of the components of these pathways has allowed man ipulation of the stress-responsive pathways and evaluation of their ph ysiological roles. These studies reveal a high degree of independence between the pathways not apparent from in vitro studies. Manipulation of the pathways in vivo will likely result in novel therapies for infl ammatory disease and reperfusion injury.