CHRONIC FOS-RELATED ANTIGENS - STABLE VARIANTS OF DELTA-FOSB INDUCED IN BRAIN BY CHRONIC TREATMENTS

Fos family transcription factors are believed to play an important rol e in the transcriptional responses of the brain to a variety of stimul i. Previous studies have described 35 and 37 kDa Fos-like proteins, te rmed chronic Fos-related antigens (FRAs), that are induced in brain in a region-specific manner in response to several chronic perturbations , including chronic electroconvulsive seizures, psychotropic drug trea tments, and lesions. We show in this study that the chronic FRAs are i soforms of Delta FosB, a truncated splice variant of FosB that accumul ate in brain after chronic treatments because of their stability. Delt a FosB cDNA encodes the expression of 33, 35, and 37 kDa proteins that arise from a single AUG translation start site. The 35 and 37 kDa pro teins correspond to the chronic FRAs that are induced in brain by chro nic treatments, whereas the 33 kDa protein corresponds to a Fos-like p rotein that is induced in brain by acute treatments, findings based on migration on one- and two-dimensional Western blots with anti-FRA and anti-FosB antibodies. Using cells in which Delta FosB or FosB express ion is under the control of a tetracycline-regulated gene expression s ystem, we show that the 37 kDa Delta FosB protein exhibits a remarkabl y long half-life, the 35 kDa Delta FosB protein exhibits an intermedia te half-life, and the 33 kDa Delta FosB protein and all FosH-derived p roteins exhibit relatively short half-lives. Moreover, we show that th e 33 kDa Delta FosB protein is the first to appear after activation of Delta FosB expression. Finally, Delta FosB proteins are shown to poss ess DNA-binding activity and to exert potent transactivating effects i n reporter gene assays. Together, these findings support a scheme wher ein Delta FosB, expressed as a 33 kDa protein, is modified to form hig hly stable isoforms of 35 and 37 kDa. As a result, these stable isofor ms gradually accumulate in the brain with repeated treatments to media te forms of long-lasting neural and behavioral plasticity.