FOSB

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FBJ murine osteosarcoma viral oncogene homolog B
Identifiers
Symbols FOSB ; AP-1; G0S3; GOS3; GOSB
External IDs OMIM164772 MGI95575 HomoloGene31403 GeneCards: FOSB Gene
RNA expression pattern
PBB GE FOSB 202768 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2354 14282
Ensembl ENSG00000125740 ENSMUSG00000003545
UniProt P53539 P13346
RefSeq (mRNA) NM_001114171 NM_008036
RefSeq (protein) NP_001107643 NP_032062
Location (UCSC) Chr 19:
45.97 – 45.98 Mb
Chr 7:
19.3 – 19.31 Mb
PubMed search [1] [2]

FBJ murine osteosarcoma viral oncogene homolog B also known as FOSB or FosB is a protein that, in humans, is encoded by the FOSB gene.[1][2][3]

The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.[1]

ΔFosB[edit]

ΔFosB or Delta FosB is a truncated splice variant of FosB.[4] Delta FosB has been implicated in the development of drug addiction and control of the reward system in the brain, and is linked to changes in a number of other gene products such as CREB and sirtuins.[5][6][7][8][9][10] Delta FosB also regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.[11] ΔJunD is the transcription factor which directly opposes ΔFosB.[12]

Role in drug addiction[edit]

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain.[12][13] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[12] ΔFosB is the most significant, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[12] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, and substituted amphetamines.[12][13][14] ΔJunD is the transcription factor which directly opposes ΔFosB.[12] Increases in nucleus accumbens ΔJunD expression can reduce or, with a large increase, even block most of the neural alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[12] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[12][13] Since natural rewards, like drugs of abuse, induce ΔFosB, chronic acquisition of these rewards can result in a similar pathological addictive state.[12][13] Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction, especially amphetamine-induced sex addictions.[12][13][15] ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.[16]

Cocaine use[edit]

Delta FosB levels have been found to increase upon the use of cocaine.[17] Each subsequent dose of cocaine will continue to increase the levels of Delta FosB with no ceiling of tolerance. Increasing the levels of Delta FosB has led to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn will increase the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug. This consequence of cocaine use may attribute to the idea of sensitization presented with the drug.

Transgenic mice exhibiting inducible expression of delta FosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to drugs.[18] They self-administer cocaine at lower doses than control,[19] but have a greater likelihood of relapse when the drug is withheld.[19][20] Delta FosB increases the expression of AMPA receptor subunit GluR2[18] and also decreases expression of dynorphin, thereby enhancing the sensitivity to reward.[20]

See also[edit]

References[edit]

  1. ^ a b "Entrez Gene: FOSB FBJ murine osteosarcoma viral oncogene homolog B". 
  2. ^ Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (October 1990). "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 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID 1702972. 
  3. ^ Martin-Gallardo A, McCombie WR, Gocayne JD, FitzGerald MG, Wallace S, Lee BM, Lamerdin J, Trapp S, Kelley JM, Liu LI (April 1992). "Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3". Nat. Genet. 1 (1): 34–9. doi:10.1038/ng0492-34. PMID 1301997. 
  4. ^ Nakabeppu Y, Nathans D (February 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell 64 (4): 751–9. doi:10.1016/0092-8674(91)90504-R. PMID 1900040. 
  5. ^ Werme M, Messer C, Olson L, et al. (2002). "Delta FosB regulates wheel running". J. Neurosci. 22 (18): 8133–8. PMID 12223567. 
  6. ^ McClung CA, Nestler EJ (November 2003). "Regulation of gene expression and cocaine reward by CREB and DeltaFosB". Nature Neuroscience 6 (11): 1208–15. doi:10.1038/nn1143. PMID 14566342. 
  7. ^ Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 363 (1507): 3245–55. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. 
  8. ^ Renthal W, Carle TL, Maze I, Covington HE, Truong HT, Alibhai I, Kumar A, Montgomery RL, Olson EN, Nestler EJ (July 2008). "Delta FosB mediates epigenetic desensitization of the c-fos gene after chronic amphetamine exposure". Journal of Neuroscience 28 (29): 7344–9. doi:10.1523/JNEUROSCI.1043-08.2008. PMC 2610249. PMID 18632938. 
  9. ^ Renthal W, Nestler EJ (August 2008). "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine 14 (8): 341–50. doi:10.1016/j.molmed.2008.06.004. PMC 2753378. PMID 18635399. 
  10. ^ Renthal W, Kumar A, Xiao G, Wilkinson M, Covington HE, Maze I, Sikder D, Robison AJ, LaPlant Q, Dietz DM, Russo SJ, Vialou V, Chakravarty S, Kodadek TJ, Stack A, Kabbaj M, Nestler EJ (May 2009). "Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins". Neuron 62 (3): 335–48. doi:10.1016/j.neuron.2009.03.026. PMC 2779727. PMID 19447090. 
  11. ^ Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (September 2000). "Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis.". Nature Medicine 6 (9): 985–90. doi:10.1038/79683. PMID 10973317. 
  12. ^ a b c d e f g h i j Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clin Psychopharmacol Neurosci 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. "ΔFosB has been linked directly to several addiction-related behaviors ...  Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states." 
  13. ^ a b c d e Hyman SE, Malenka RC, Nestler EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. 
  14. ^ Kanehisa Laboratories (2 August 2013). "Alcoholism - Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014. 
  15. ^ Pitchers KK, Frohmader KS, Vialou V, Mouzon E, Nestler EJ, Lehman MN, Coolen LM (October 2010). "ΔFosB in the nucleus accumbens is critical for reinforcing effects of sexual reward". Genes Brain Behav. 9 (7): 831–840. doi:10.1111/j.1601-183X.2010.00621.x. PMC 2970635. PMID 20618447. 
  16. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 384–385. ISBN 9780071481274. 
  17. ^ Hope BT (May 1998). "Cocaine and the AP-1 transcription factor complex". Ann. N. Y. Acad. Sci. 844: 1–6. doi:10.1111/j.1749-6632.1998.tb08216.x. PMID 9668659. 
  18. ^ a b Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Surmeier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (September 1999). "Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine". Nature 401 (6750): 272–6. doi:10.1038/45790. PMID 10499584. 
  19. ^ a b Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW (March 2003). "Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine". J. Neurosci. 23 (6): 2488–93. PMID 12657709. 
  20. ^ a b Nestler EJ, Barrot M, Self DW (September 2001). "DeltaFosB: a sustained molecular switch for addiction". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11042–6. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.