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HGNC Approved Gene Symbol: FOSB
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:45,467,996-45,475,179 (from NCBI)
The human FOSB sequence was determined on the basis of cDNA cloned from mRNA rapidly induced in cultured human blood lymphocyte cultures treated with lectin and cycloheximide. The gene was initially named G0S3 (Siderovski et al., 1990). Subsequent database searches (Forsdyke, 1992) established high homology to murine Fosb, and cDNA and genomic sequences were almost identical to the human FOSB sequence of Martin-Gallardo et al. (1992).
Martin-Gallardo et al. (1992) assembled the complete sequence for a 105,831 bp segment of 19q13.3. They concluded that it contained a segment of 19q13.3 surrounding the ERCC1 gene (126380). A portion of the segment predicted an amino acid sequence 95.6% identical and 99.4% similar to the protein encoded by a previously sequenced cDNA from the mouse Fosb serum-inducible protooncogene. These data strongly suggested that this gene, which was immediately preceded by a CpG island, was the human FOSB gene. This idea was consistent with the homology of synteny observed between 19q13 and the proximal region of mouse chromosome 7, to which the mouse Fosb gene was mapped by Lazo et al. (1992).
Nakabeppu and Nathans (1991) identified an unusual member of the FOS family that is induced, namely, a truncated form of FOSB called delta-FOSB, missing the C-terminal 101 amino acids of FOSB. Delta-FOSB retains the dimerization and DNA binding activities of FOSB but has lost the ability in transfection assays to activate a promoter with an AP1 site and to repress the C-FOS promoter. Delta-FOSB inhibited gene activation by JUN (165160) or the JUN/FOS complex and inhibited repression of the C-FOS promoter by FOSB or C-FOS, presumably by competing with full-length FOS proteins at the steps of dimerization with JUN and binding to DNA. Nakabeppu and Nathans (1991) concluded that in stimulated cells, delta-FOSB may act to limit the transcriptional effects of FOS and JUN proteins.
Acute exposure to cocaine transiently induces several FOS family transcription factors in the nucleus accumbens, the region of the brain that is important for addiction. In contrast, chronic exposure to cocaine does not induce these proteins but instead causes the persistent expression of highly stable isoforms of delta-FOSB. Delta-FOSB is also induced in the nucleus accumbens by repeated exposure to other drugs of abuse, including amphetamine, morphine, nicotine, and phencyclidine, or PCP. The sustained accumulation of delta-FOSB in the nucleus accumbens indicated that this transcription factor may mediate some of the persistent neural and behavioral plasticity that accompanies chronic drug exposure. Using transgenic mice in which delta-FOSB can be induced in adults in the subset of nucleus accumbens neurons in which cocaine induces the protein, Kelz et al. (1999) demonstrated that delta-FOSB expression increases the responsiveness of an animal to the rewarding and locomotor-activating effects of cocaine. These effects of delta-FOSB appeared to be mediated partly by induction of the AMPA glutamate receptor subunit GluR2 (138247) in the nucleus accumbens. Kelz et al. (1999) concluded that these results supported a model in which delta-FOSB, by altering gene expression, enhances sensitivity to cocaine and may thereby contribute to cocaine addiction.
Cocaine enhances dopamine-mediated neurotransmission by blocking dopamine reuptake at axon terminals. Most dopamine-containing nerve terminals innervate medium spiny neurons in the striatum of the brain. Cocaine addiction is thought to stem, in part, from neural adaptations that act to maintain equilibrium by countering the effects of repeated drug administration. Chronic exposure to cocaine upregulates several transcription factors that alter gene expression and which could mediate such compensatory neural and behavioral changes. One such transcription factor is delta-FosB, a protein that persists in striatum long after the end of cocaine exposure. Using DNA array analysis of striatal material from inducible transgenic mice, Bibb et al. (2001) identified Cdk5 (123831) as a downstream target of delta-FosB. Overexpression of delta-FosB, or chronic cocaine administration, raised levels of Cdk5 mRNA, protein, and activity in the striatum. Moreover, injection of Cdk5 inhibitors into the striatum potentiated behavioral effects of repeated cocaine administration. Bibb et al. (2001) concluded that changes in Cdk5 levels mediated by delta-FosB, and resulting alterations in signaling involving D1 dopamine receptors, contribute to adaptive changes in the brain related to cocaine addiction.
Maze et al. (2010) identified an essential role for histone-3 lysine-9 (H3K9) dimethylation and the lysine dimethyltransferase G9a (604599) in cocaine-induced structural and behavioral plasticity in mouse. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor delta-FosB. Using conditional mutagenesis and viral-mediated gene transfer, Maze et al. (2010) found that G9a downregulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.
Brown et al. (1996) demonstrated that mice in whom the FOSB gene had been inactivated by homologous recombination displayed a profound defect in reproduction. The reproductive failure of fosB mutant mice was due to a specific behavioral defect that resulted in an inability to nurture young. This nurturing defect was seen not only in postpartum females but also in young females and males. Together, these findings provided evidence that nurturing behavior in mammals is genetically controlled and that an immediate early gene, FOSB, is critical for an adaptive neuronal response. Brown et al. (1996) speculated that the nurturing defect is likely due to the absence of FOSB in the preoptic area, a region of the hypothalamus that is critical for nurturing. They stated that this is an example of a transcription factor that controls a complex behavior by regulating a specific neuronal circuit.
Bibb, J. A., Chen, J., Taylor, J. R., Svenningsson, P., Nishi, A., Snyder, G. L., Yan, Z., Sagawa, Z. K., Ouimet, C. C., Nairn, A. C., Nestler, E. J., Greengard, P. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410: 376-380, 2001. [PubMed: 11268215] [Full Text: https://doi.org/10.1038/35066591]
Brown, J. R., Ye, H., Bronson, R. T., Dikkes, P., Greenberg, M. E. A defect in nurturing in mice lacking the immediate early gene fosB. Cell 86: 297-309, 1996. [PubMed: 8706134] [Full Text: https://doi.org/10.1016/s0092-8674(00)80101-4]
Forsdyke, D. Personal Communication. Kingston, Ontario, Canada 6/8/1992.
Kelz, M. B., Chen, J., Carlezon, W. A., Jr., Whisler, K., Gilden, L., Beckmann, A. M., Steffen, C., Zhang, Y.-J., Marotti, L., Self, D. W., Tkatch, T., Baranauskas, G., Surmeier, D. J., Neve, R. L., Duman, R. S., Picciotto, M. R., Nestler, E. J. Expression of the transcription factor delta-FosB in the brain controls sensitivity to cocaine. Nature 401: 272-276, 1999. [PubMed: 10499584] [Full Text: https://doi.org/10.1038/45790]
Lazo, P. S., Dorfman, K., Noguchi, T., Mattei, M. G., Bravo, R. Structure and mapping of the fosB gene: FosB downregulates the activity of the fosB promoter. Nucleic Acids Res. 20: 343-350, 1992. [PubMed: 1741260] [Full Text: https://doi.org/10.1093/nar/20.2.343]
Martin-Gallardo, A., McCombie, W. R., Gocayne, J. D., FitzGerald, M. G., Wallace, S., Lee, B. M. B., Lamerdin, J., Trapp, S., Kelley, J. M., Liu, L.-I., Dubnick, M., Johnston-Dow, L. A., Kerlavage, A. R., de Jong, P., Carrano, A., Fields, C., Venter, J. C. Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3. Nature Genet. 1: 34-39, 1992. [PubMed: 1301997] [Full Text: https://doi.org/10.1038/ng0492-34]
Maze, I., Covington, H. E., III, Dietz, D. M., LaPlant, Q., Renthal, W., Russo, S. J., Mechanic, M., Mouzon, E., Neve, R. L., Haggarty, S. J., Ren, Y., Sampath, S. C., Hurd, Y. L., Greengard, P., Tarakhovsky, A., Schaefer, A., Nestler, E. J. Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327: 213-216, 2010. [PubMed: 20056891] [Full Text: https://doi.org/10.1126/science.1179438]
Nakabeppu, Y., Nathans, D. A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity. Cell 64: 751-759, 1991. [PubMed: 1900040] [Full Text: https://doi.org/10.1016/0092-8674(91)90504-r]
Siderovski, D. P., Blum, S., Forsdyke, R. E., Forsdyke, D. R. A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes. DNA Cell Biol. 9: 579-587, 1990. [PubMed: 1702972] [Full Text: https://doi.org/10.1089/dna.1990.9.579]