PT  - JOURNAL ARTICLE
AU  - Jingshan Chen
AU  - Max B. Kelz
AU  - Bruce T. Hope
AU  - Yusaku Nakabeppu
AU  - Eric J. Nestler
TI  - Chronic Fos-Related Antigens: Stable Variants of ΔFosB Induced in Brain by Chronic Treatments
AID  - 10.1523/JNEUROSCI.17-13-04933.1997
DP  - 1997 Jul 01
TA  - The Journal of Neuroscience
PG  - 4933--4941
VI  - 17
IP  - 13
4099  - http://www.jneurosci.org/content/17/13/4933.short
4100  - http://www.jneurosci.org/content/17/13/4933.full
SO  - J. Neurosci.1997 Jul 01; 17
AB  - Fos family transcription factors are believed to play an important role in the transcriptional responses of the brain to a variety of stimuli. Previous studies have described 35 and 37 kDa Fos-like proteins, termed 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 treatments, and lesions. We show in this study that the chronic FRAs are isoforms of ΔFosB, a truncated splice variant of FosB that accumulate in brain after chronic treatments because of their stability. ΔFosB 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 proteins correspond to the chronic FRAs that are induced in brain by chronic treatments, whereas the 33 kDa protein corresponds to a Fos-like protein 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 ΔFosB or FosB expression is under the control of a tetracycline-regulated gene expression system, we show that the 37 kDa ΔFosB protein exhibits a remarkably long half-life, the 35 kDa ΔFosB protein exhibits an intermediate half-life, and the 33 kDa ΔFosB protein and all FosB-derived proteins exhibit relatively short half-lives. Moreover, we show that the 33 kDa ΔFosB protein is the first to appear after activation of ΔFosB expression. Finally, ΔFosB proteins are shown to possess DNA-binding activity and to exert potent transactivating effects in reporter gene assays. Together, these findings support a scheme wherein ΔFosB, expressed as a 33 kDa protein, is modified to form highly stable isoforms of 35 and 37 kDa. As a result, these stable isoforms gradually accumulate in the brain with repeated treatments to mediate forms of long-lasting neural and behavioral plasticity.