Dimerization and DNA-Binding Properties of the Transcription Factor ΔFosB

Abstract

The transcription factor, DeltaFosB, a splice isoform of fosB, accumulates in rodents in a brain-region-specific manner in response to chronic administration of drugs of abuse, stress, certain antipsychotic or antidepressant medications, electroconvulsive seizures, and certain lesions. Increasing evidence supports a functional role of such DeltaFosB induction in animal models of several psychiatric and neurologic disorders. Fos family proteins, including DeltaFosB, are known to heterodimerize with Jun family proteins to create active AP-1 transcription-factor complexes, which bind to DNA specifically at AP-1 consensus sites. We show here, using a range of biochemical and biophysical means, that recombinant, purified DeltaFosB forms homodimers as well, at concentrations less than 500 nM, and that these homodimers specifically bind to DNA oligonucleotides containing AP-1 consensus sequences in the absence of any Jun partner. Our results suggest that, as DeltaFosB accumulates to abnormally elevated protein levels in highly specific regions of the brain in response to chronic stimulation, functional homodimers of DeltaFosB are formed with the potential to uniquely regulate patterns of gene expression and thereby contribute to the complex processes of neural and behavioral adaptation.

Overexpression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair-deficient/cancer-prone xeroderma pigmentosum group C patients

“…In contrast, DNA-binding and protein expression of P-c-JUN appeared both slightly decreased. These observations could be connected to the capacity of the FOSB2 isoform to form functional homodimers (Jorissen et al, 2007). Alternatively, under some stress circumstances related to acidification, FOSB has been shown to functionally heterodimerize with MafG in DNA-binding complexes (Shimokawa et al, 2005).…”

The role of ΔfosB in the medial preoptic area: Differential effects of mating and cocaine history.

“…Subjects received bilateral intracranial microinjections of adeno-associated viral vectors (AAV) encoding green fluorescent protein (GFP, n = 18), wild-type ΔFosB and GFP (ΔFosB, n = 18), or ΔJunD and GFP (ΔJunD, n = 18). ΔFosB heterodimerizes with JunD to form an AP-1; thus the truncated ΔJunD, which lacks a DNA binding domain, is a dominant negative antagonist of ΔFosB-mediated transcription (Jorissen et al, 2007; Nestler, 2008; Winstanley et al, 2007). Animals were tested for sexual behavior on three occasions, each 1 week apart, beginning 5 weeks after microinjections of AAV vectors to ensure ample time for transfection and stable viral expression.…”

Transcriptional and epigenetic mechanisms of addiction

“…It heterodimerizes with Jun family proteins to form activator protein 1 (AP-1) complexes that bind to AP-1 sites in responsive genes to regulate transcription. There is some evidence from in vitro studies that ΔFosB may also homodimerize 15 . Although all Fos family proteins are induced transiently by acute drug exposure, chronic administration of virtually any drug of abuse induces the long-lasting expression specifically of ΔFosB 14,16,17 , a process most robust in the NAc and dorsal striatum, but also seen in several other reward-related brain regions including prefrontal cortex 16 .…”