Alterations in gene expression as an index of neuronal injury: heat shock and the immediate early gene response.

The c-fos immediate early gene is induced by normal stimuli including light, stress, hyperosmolar solutions, and hormones. Ischemia, hypoxia, seizures, cortical injury, nerve section and other pathological stimuli can also induce c-fos. The induction can occur via increases in intracellular calcium that act through a Ca2+/cAMP element on its promoter, or via trophic and other factors that act through a serum response element (SRE) on its promoter. Several studies show that calcium entry via voltage sensitive calcium channels (VSCCs) is important for inducing c-fos. We have shown that calcium entry via the NMDA receptor is important for induction of c-fos mRNA by glutamate and cAMP in cultured cortical neurons. Moreover, the NMDA receptor appears to regulate translation of c-fos mRNA to Fos protein when cells are stimulated with other types of stimuli including vasoactive intestinal peptide, zinc, and fibroblast growth factor. These results suggest that toxins that elevate intracellular calcium will likely induce the c-fos gene in brain. The heat shock or stress genes are induced by a wide variety of stimuli including heavy metals, heat, oxidative and ischemic stress, prolonged seizures, hypoglycemia, calcium ionophores, and certain toxins. It is believed that denatured proteins stimulate heat shock factors to bind to heat shock elements on the promoters of all heat shock genes to induce gene transcription. We and others have shown that global and focal ischemia induce the hsp70 heat shock gene in brain. Mild ischemia induces hsp70 mRNA and HSP70 protein in neurons only.(ABSTRACT TRUNCATED AT 250 WORDS)