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Volume 17, Number 13, Issue of July 1, 1997 pp. 4933-4941
Copyright ©1997 Society for Neuroscience

Chronic Fos-Related Antigens: Stable Variants of FosB Induced in Brain by Chronic Treatments

Received Feb. 7, 1997; revised April 3, 1997; accepted April 11, 1997.

Jingshan Chen¹, Max B. Kelz¹, Bruce T. Hope², Yusaku Nakabeppu³, and Eric J. Nestler¹

¹ Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut 06508, ² National Institute of Mental Health, Bethesda, Maryland 20892, and ³ Kyushu University, Fukuoka 812, Japan

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 FosB, a truncated splice variant of FosB that accumulate in brain after chronic treatments because of their stability. 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 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 FosB or FosB expression is under the control of a tetracycline-regulated gene expression system, we show that the 37 kDa FosB protein exhibits a remarkably long half-life, the 35 kDa FosB protein exhibits an intermediate half-life, and the 33 kDa FosB protein and all FosB-derived proteins exhibit relatively short half-lives. Moreover, we show that the 33 kDa FosB protein is the first to appear after activation of FosB expression. Finally, FosB 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 FosB, 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.

Key words: seizure; cocaine; FosB; chronic Fos-related antigens; gene expression; neural plasticity

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