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]

Its truncated splice variant, ΔFosB, has been identified as playing a central, crucial (necessary and sufficient)[4] role in the development of many forms of behavioral plasticity and neuroplasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions.[5]

ΔFosB[edit]

ΔFosB or Delta FosB is a truncated splice variant of FosB.[6] ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and drug addictions.[4][7][8] In the brain's reward system, it is linked to changes in a number of other gene products, such as CREB and sirtuins.[9][10][11] In the body, ΔFosB regulates the commitment of mesenchymal precursor cells to the adipocyte or osteoblast lineage.[12]

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methylphenidate, and phenethylamine, and cocaine. Following presynaptic dopamine and glutamate co-release by a drug, postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[13][14] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors.[14] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated exposure to stimulants through this process.[15][16] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[15][16]


Role in addiction[edit]

Current models of addiction from chronic drug use involve alterations in gene expression in the mesocorticolimbic projection.[4][17][18] 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).[4] ΔFosB is the most significant gene transcription factor in addiction since its viral or genetic overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[4] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, opiates, and substituted amphetamines.[4][17][19] ΔJunD is the transcription factor which directly opposes ΔFosB.[4] 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).[4]

ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[4][7] Natural rewards, like drugs of abuse, induce ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.[4][7][8] Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards as well;[4][7][8] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[7] Research on the interaction between natural and drug rewards suggests that psychostimulants and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess cross-sensitization effects that are mediated through ΔFosB.[5][8]

ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.[20]

Cocaine use[edit]

ΔFosB levels have been found to increase upon the use of cocaine.[21] Each subsequent dose of cocaine continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (BDNF) levels, which in turn increases 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 contribute to sensitization to the drug.

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal striatum exhibit sensitized behavioural responses to cocaine.[22] They self-administer cocaine at lower doses than control,[23] but have a greater likelihood of relapse when the drug is withheld.[23][24] ΔFosB increases the expression of AMPA receptor subunit GluR2[22] and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.[24]

Role in depression[edit]

ΔFosB expression in the nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to social defeat stress.[25][26]

Summary of addiction-related plasticity[edit]

Form of neural or behavioral plasticity Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual reward Exercise Environmental enrichment
ΔFosB expression
in the nucleus accumbens
[8]
Behavioral Plasticity
Escalation of intake Yes Yes Yes [8]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [8]
Psychostimulant
self-administration
[8]
Psychostimulant
conditioned place preference
[8]
Reinstatement of drug-seeking behavior [8]
Neurochemical Plasticity
CREB phosphorylation
in the nucleus accumbens
[8]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [8]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [8]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [8]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [8]
Mesocorticolimbic Synaptic Plasticity
Number of dendrites in the nucleus accumbens [8]
Dendritic spine density in
the nucleus accumbens
No change [8]

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): 579–587. 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): 34–39. doi:10.1038/ng0492-34. PMID 1301997. 
  4. ^ a b c d e f g h i j k Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. "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." 
  5. ^ a b Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. "Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity" 
  6. ^ Nakabeppu Y, Nathans D (February 1991). "A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity". Cell 64 (4): 751–759. doi:10.1016/0092-8674(91)90504-R. PMID 1900040. 
  7. ^ a b c d e Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964. "It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry." 
  8. ^ a b c d e f g h i j k l m n o p q Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Retrieved September 10, 2014. "Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ...
    Table 1"
     
  9. ^ 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): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. 
  10. ^ Renthal W, Nestler EJ (August 2008). "Epigenetic mechanisms in drug addiction". Trends in Molecular Medicine 14 (8): 341–350. doi:10.1016/j.molmed.2008.06.004. PMC 2753378. PMID 18635399. 
  11. ^ 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): 335–348. doi:10.1016/j.neuron.2009.03.026. PMC 2779727. PMID 19447090. 
  12. ^ 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): 985–990. doi:10.1038/79683. PMID 10973317. 
  13. ^ Kanehisa Laboratories (27 February 2012). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 21 July 2014. 
  14. ^ a b Renthal W, Nestler EJ (2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268. PMC 2834246. PMID 19877494. Retrieved 21 July 2014. 
  15. ^ a b Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. "ΔFosB serves as one of the master control proteins governing this structural plasticity." 
  16. ^ a b 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. "The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB" 
  17. ^ a b 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. 
  18. ^ Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Prog. Neurobiol. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425. 
  19. ^ Kanehisa Laboratories (2 August 2013). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 10 April 2014. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ 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): 272–276. doi:10.1038/45790. PMID 10499584. 
  23. ^ 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): 2488–2493. PMID 12657709. 
  24. ^ 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): 11042–11046. doi:10.1073/pnas.191352698. PMC 58680. PMID 11572966. 
  25. ^ "ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS". Mount Sinai School of Medicine. NESTLER LAB: LABORATORY OF MOLECULAR PSYCHIATRY. Retrieved 6 September 2014. "Role of ΔFosB in Depression
    More recently, we have shown that induction of ΔFosB in nucleus accumbens in response to chronic stress represents a positive, adaptive mechanism to help the animal cope with the stress. In the social defeat paradigm, for example, animalsthat are resilient to the deleterious effects of defeat stress show greater induction of ΔFosB than vulnerable animals. Moreover, chronic administration of antidepressant medications induces ΔFosB in nucleus accumbens and the behavioral effects of these treatments can be blocked by blockade of ΔFosB activity in this brain region. Together, these data demonstrate that ΔFosB is a novel mechanism of resilience and a potentially important mediator of antidepressant action. ...
    Interesting comparisons and contrasts with CREB are evident. Both ΔFosB and CREB are induced by stress and by drugs of abuse, yet they exert opposite effects on behavior. CREB reduces behavioral responses to emotional stimuli and induces a depression-like state in the extreme, whereas ΔFosB sensitizes reward and induces antidepressant-like responses. Also, the CREB signal is relatively short-lived, while the ΔFosB signal is long-lived."
     
  26. ^ Furuyashiki T, Deguchi Y (August 2012). "[Roles of altered striatal function in major depression]". Brain Nerve (in Japanese) 64 (8): 919–26. PMID 22868883. 
Image legend
  1. ^
      Ion channel
      G-proteins & linked receptors
      (Text color) Transcription factors

Further reading[edit]

External links[edit]

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