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Title: C-Fos  
Author: World Heritage Encyclopedia
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Subject: AP-1 transcription factor, C-jun, Activating transcription factor, FOSB, Addiction
Collection: Addiction, Oncogenes, Transcription Factors
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FBJ murine osteosarcoma viral oncogene homolog
Structure of NFAT(green), Jun(blue) and Fos(red) bound to DNA. Based on PDB entry .
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; AP-1; C-FOS; p55
External IDs ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

In the fields of molecular biology and genetics, c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos.[1] It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Jinkins murine osteogenic sarcoma virus). It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2 as well as smaller FosB splice variants, FosB2 and ΔFosB.[2] It has been mapped to chromosome region 14q21→q31. C-fos encodes a 62 kDa protein, which forms heterodimer with c-jun (part of Jun family of transcription factors), resulting in the formation of AP-1 (Activator Protein-1) complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression.[3] It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.


  • Structure and function 1
  • Clinical significance 2
  • Applications 3
  • Interactions 4
  • See also 5
  • References 6
  • Further reading 7
  • External links 8

Structure and function

c-fos is a 380 amino acid protein with a basic leucine zipper region for dimerisation and DNA-binding and a transactivation domain at C-terminus. Unlike Jun proteins, it cannot form homodimers, only heterodimers with c-jun. In vitro studies have shown that Jun–Fos heterodimers are more stable and have stronger DNA-binding activity than Jun–Jun homodimers.[4]

A variety of stimuli, including serum, growth factors, tumor promoters, cytokines, and UV radiation induce their expression. The c-fos mRNA and protein is generally among the first to be expressed and hence referred to as an immediate early gene. It is rapidly and transiently induced, within 15 minutes of stimulation.[5] Its activity is also regulated by posttranslational modification caused by phosphorylation by different kinases, like MAPK, cdc2, PKA or PKC which influence protein stability, DNA-binding activity and the trans-activating potential of the transcription factors.[6][7][8] It can cause gene repression as well as gene activation, although different domains are believed to be involved in both processes.

It is involved in important cellular events, including cell proliferation, differentiation and survival; genes associated with hypoxia; and angiogenesis;[9] which makes its dysregulation an important factor for cancer development. It can also induce a loss of cell polarity and epithelial-mesenchymal transition, leading to invasive and metastatic growth in mammary epithelial cells.[10]

The importance of c-fos in biological context has been determined by eliminating endogenous function by using anti-sense mRNA, anti-c-fos antibodies, a ribozyme that cleaves c-fos mRNA or a dominant negative mutant of c-fos. The transgenic mice thus generated are viable, demonstrating that there are c-fos dependent and independent pathways of cell proliferation, but display a range of tissue-specific developmental defects, including osteoporosis, delayed gametogenesis, lymphopenia and behavioral abnormalities.

Clinical significance

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, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[11][12] 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][15] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors;[14] c-fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[16] 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.[17][18] 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.[17][18] 

The AP-1 complex has been implicated in transformation and progression of cancer. In osteosarcoma and endometrial carcinoma, c-Fos overexpression was associated with high-grade lesions and poor prognosis. Also, in a comparison between precancerous lesion of the cervix uteri and invasive cervical cancer, c-Fos expression was significantly lower in precancerous lesions. C-Fos has also been identified as independent predictor of decreased survival in breast cancer.[19]

It was found that overexpression of c-fos from class I MHC promoter in transgenic mice leads to the formation of osteosarcomas due to increased proliferation of osteoblasts whereas ectopic expression of the other Jun and Fos proteins does not induce any malignant tumors. Activation of the c-Fos transgene in mice results in overexpression of cyclin D1, A and E in osteoblasts and chondrocytes, both in vitro and in vivo, which might contribute to the uncontrolled growth leading to tumor. Human osteosarcomas analyzed for c-fos expression have given positive results in more than half the cases and c-fos expression has been associated with higher frequency of relapse and poor response to chemotherapy.

Several studies have raised the idea that c-Fos may also have tumor-suppressor activity, that it might be able to promote as well as suppress tumorigenesis. Supporting this is the observation that in ovarian carcinomas, loss of c-Fos expression correlates with disease progression. This double action could be enabled by differential protein composition of tumour cells and their environment, for example, dimerisation partners, co-activators and promoter architecture. It is possible that the tumor suppressing activity is due to a proapoptotic function. The exact mechanism by which c-Fos contributes to apoptosis is not clearly understood, but observations in human hepatocellular carcinoma cells indicate that c-Fos is a mediator of c-myc-induced cell death and might induce apoptosis through the p38 MAP kinase pathway. Fas ligand (FASLG or FasL) and the tumour necrosis factor-related apoptosis-inducing ligand (TNFSF10 or TRAIL) might reflect an additional apoptotic mechanism induced by c-Fos, as observed in a human T-cell leukaemia cell line. Another possible mechanism of c-Fos involvement in tumour suppression could be the direct regulation of BRCA1, a well established factor in familial breast and ovarian cancer.

In addition, role of c-fos and other Fos family proteins has also been studied in endometrial carcinoma, cervical cancer, mesotheliomas, colorectal cancer, lung cancer, melanomas, thyroid carcinomas, esophageal cancer, hepatocellular carcinomas, etc.

Cocaine, methamphetamine,[20] heroin,[21] and other psychoactive drugs[22][23] have been shown to increase c-fos production in the mesocortical pathway (prefrontal cortex) as well as in the mesolimbic reward pathway (nucleus accumbens). Accumbal c-Fos repression by ΔFosB's AP-1 complex acts as a molecular switch for the long-term induction of ΔFosB, thus allowing it to accumulate in dopamine D1-type medium spiny neurons. As such, the c-Fos promoter finds utilization in drug addiction research in general, as well as with context-induced relapse to drug-seeking and other behavioral changes associated with chronic drug taking.

An increase in c-Fos production in androgen receptor-containing neurons has been observed in rats after mating.


Expression of c-fos is an indirect marker of neuronal activity because c-fos is often expressed when neurons fire action potentials.[24][25] Upregulation of c-fos mRNA in a neuron indicates recent activity.[26]

Drug abuse research also finds application of the c-fos promoter. Scientists use this promoter to turn on transgenes in rats that allow them to manipulate specific neuronal ensembles to assess their role in drug-related memories and behavior.[27] This neuronal control can be replicated with optogenetics or DREADDs [28]


C-Fos has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis.

See also


  1. ^ Curran, T: The c-fos proto-oncogene. In: Reddy EP, Skalka AM, Curran T (eds.). The Oncogene Handbook 1988 Elsevier, New York, pp 307–327,
  2. ^ Milde-Langosch K (November 2005). "The Fos family of transcription factors and their role in tumourigenesis". Eur. J. Cancer 41 (16): 2449–61.  
  3. ^ Chiu R, Boyle WJ, Meek J, Smeal T, Hunter T, Karin M (August 1988). "The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes". Cell 54 (4): 541–52.  
  4. ^ Halazonetis TD, Georgopoulos K, Greenberg ME, Leder P (December 1988). "c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities". Cell 55 (5): 917–24.  
  5. ^ Hu E, Mueller E, Oliviero S, Papaioannou VE, Johnson R, Spiegelman BM (July 1994). "Targeted disruption of the c-fos gene demonstrates c-fos-dependent and -independent pathways for gene expression stimulated by growth factors or oncogenes". EMBO J. 13 (13): 3094–103.  
  6. ^ Gruda MC, Kovary K, Metz R, Bravo R (September 1994). "Regulation of Fra-1 and Fra-2 phosphorylation differs during the cell cycle of fibroblasts and phosphorylation in vitro by MAP kinase affects DNA binding activity". Oncogene 9 (9): 2537–47.  
  7. ^ Hurd TW, Culbert AA, Webster KJ, Tavaré JM (December 2002). "Dual role for mitogen-activated protein kinase (Erk) in insulin-dependent regulation of Fra-1 (fos-related antigen-1) transcription and phosphorylation". Biochem. J. 368 (Pt 2): 573–80.  
  8. ^ Rosenberger SF, Finch JS, Gupta A, Bowden GT (January 1999). "Extracellular signal-regulated kinase 1/2-mediated phosphorylation of JunD and FosB is required for okadaic acid-induced activator protein 1 activation". J. Biol. Chem. 274 (2): 1124–30.  
  9. ^ Tulchinsky E (July 2000). "Fos family members: regulation, structure and role in oncogenic transformation". Histol. Histopathol. 15 (3): 921–8.  
  10. ^ Fialka I, Schwarz H, Reichmann E, Oft M, Busslinger M, Beug H (March 1996). "The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions". J. Cell Biol. 132 (6): 1115–32.  
  11. ^ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 139 (1): 93–96.  
  12. ^ Descarries L, Berube-Carriere N, Riad M, Bo GD, Mendez JA, Trudeau LE (August 2008). "Glutamate in dopamine neurons: synaptic versus diffuse transmission". Brain Res. Rev. 58 (2): 290–302.  
  13. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. 
  14. ^ a b Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues Clin. Neurosci. 11 (3): 257–268.  
  15. ^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Mol. Neurobiol. 51 (2): 696–717.  
  16. ^ Nestler EJ (October 2008). "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 363 (1507): 3245–3255.  
  17. ^ a b Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637.  
  18. ^ a b Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clin. Psychopharmacol. Neurosci. 10 (3): 136–143.  
  19. ^ Mahner S, Baasch C, Schwarz J, Hein S, Wölber L, Jänicke F, Milde-Langosch K (October 2008). "C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma". Br. J. Cancer 99 (8): 1269–75.  
  20. ^ Graybiel AM, Moratalla R, Robertson HA (September 1990). "Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum". Proc. Natl. Acad. Sci. U.S.A. 87 (17): 6912–6.  
  21. ^ Curran EJ, Akil H, Watson SJ (November 1996). "Psychomotor stimulant- and opiate-induced c-fos mRNA expression patterns in the rat forebrain: comparisons between acute drug treatment and a drug challenge in sensitized animals". Neurochem. Res. 21 (11): 1425–35.  
  22. ^ Nichols CD, Sanders-Bush E (May 2002). "A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain". Neuropsychopharmacology 26 (5): 634–42.  
  23. ^ Singewald N, Salchner P, Sharp T (February 2003). "Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs". Biol. Psychiatry 53 (4): 275–83.  
  24. ^ VanElzakker M, Fevurly RD, Breindel T, Spencer RL (2008). "Environmental novelty is associated with a selective increase in c-fos expression in the output elements of the hippocampal formation and the perirhinal cortex". Learn. Mem. 15 (12): 899–908.  
  25. ^ Dragunow M, Faull R (1989). "The use of c-fos as a metabolic marker in neuronal pathway tracing". Journal of Neuroscience Methods 29 (3): 261–265.  
  26. ^ Day HE, Kryskow EM, Nyhuis TJ, Herlihy L, Campeau S (September 2008). "Conditioned Fear Inhibits c-fos mRNA Expression in the Central Extended Amygdala". Brain Res. 1229: 137–46.  
  27. ^ Koya E, Golden SA, Harvey BK, Guez-Barber DH, Berkow A, Simmons DE, Bossert JM, Nair SG, Uejima JL, Marin MT, Mitchell TB, Farquhar D, Ghosh SC, Mattson BJ, Hope BT (August 2009). "Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization". Nat. Neurosci. 12 (8): 1069–73.  
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  30. ^ Zhong H, Zhu J, Zhang H, Ding L, Sun Y, Huang C, Ye Q (December 2004). "COBRA1 inhibits AP-1 transcriptional activity in transfected cells". Biochem. Biophys. Res. Commun. 325 (2): 568–73.  
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  33. ^ a b Yang X, Chen Y, Gabuzda D (September 1999). "ERK MAP kinase links cytokine signals to activation of latent HIV-1 infection by stimulating a cooperative interaction of AP-1 and NF-kappaB". J. Biol. Chem. 274 (39): 27981–8.  
  34. ^ Ito T, Yamauchi M, Nishina M, Yamamichi N, Mizutani T, Ui M, Murakami M, Iba H (January 2001). "Identification of SWI.SNF complex subunit BAF60a as a determinant of the transactivation potential of Fos/Jun dimers". J. Biol. Chem. 276 (4): 2852–7.  
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Further reading

  • Murphy LC, Alkhalaf M, Dotzlaw H, Coutts A, Haddad-Alkhalaf B (June 1994). "Regulation of gene expression in T-47D human breast cancer cells by progestins and antiprogestins". Hum. Reprod. 9 Suppl 1: 174–80.  
  • Pompeiano M, Cirelli C, Arrighi P, Tononi G (1995). "c-Fos expression during wakefulness and sleep". Neurophysiol Clin 25 (6): 329–41.  
  • Herrera DG, Robertson HA (October 1996). "Activation of c-fos in the brain". Prog. Neurobiol. 50 (2–3): 83–107.  
  • Velazquez Torres A, Gariglio Vidal P (2002). "[Possible role of transcription factor AP1 in the tissue-specific regulation of human papillomavirus]". Rev. Invest. Clin. (in Spanish) 54 (3): 231–42.  

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