ENHANCED SERUM RESPONSE ELEMENT-BINDING ACTIVITY CORRELATES WITH DOWN-REGULATION OF C-FOS MESSENGER-RNA EXPRESSION IN THE RAT-BRAIN FOLLOWING REPEATED CORTICAL-LESIONS

Repeated lesions of rat cerebral cortex result in transient peaks in t he level of the c-fos transcript, but after the second lesion, this pe ak is substantially diminished. Using this lesion paradigm, we have an alyzed the participation of the c-fos promoter elements SRE and DSE in the regulation of c-fos transcription. Following a single lesion, SRE /DSE binding activity peaked at 2 h, subsequent to the maximal levels of c-fos mRNA and parallel to the peak of c-Fos protein. After a secon d lesion (reinduction), 4 h following the initial lesion, SRE/DSE bind ing activity peaked after only 30 min and was significantly higher tha n following the first lesion. Once again, this peak occurred after the peak of c-fos mRNA expression and parallel with the second peak of c- Fos protein expression. These results suggested that the SRE and DSE p romoter elements participated in the induction and down-regulation of c-fos transcription in vivo and suggested the possible involvement of Fos protein in its own regulation. The ability of Fos/Fra proteins to participate in a transcriptional complex was confirmed in gel-shift ex periments with an AP-1 element, and the biphasic trend of binding acti vity was observed. Supershift experiments were performed to directly d etermine whether Fos protein was participating in SRE and/or DSE trans criptional complexes. No alterations in the position or intensity of t he shifted band were observed using Fos/Fra antiserum suggesting that Fos/Fra proteins could be involved in c-fos down-regulation through me chanisms other than direct participation in the SRE/DSE transcription complex. (C) 1997 Elsevier Science B.V.