Protein c-Fos
Ensembl | |||||||||
---|---|---|---|---|---|---|---|---|---|
UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 14: 75.28 – 75.28 Mb | Chr 12: 85.52 – 85.52 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Protein c-Fos is a
Structure and function
c-Fos is a 380 amino acid protein with a basic
A variety of stimuli, including
It is involved in important cellular events, including cell proliferation, differentiation and survival; genes associated with
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 |
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.[23]
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, the 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,
An increase in c-Fos production in androgen receptor-containing neurons has been observed in rats after mating.[citation needed]
Applications
Expression of c-fos is an indirect marker of neuronal activity because c-fos is often expressed when neurons fire action potentials.[28][29][30] Up-regulation of c-fos mRNA in a neuron is considered a marker for activity.[31]
The c-fos promoter has also been utilized for drug abuse research. Scientists use this promoter to turn on transgenes in rats, allowing them to manipulate specific neuronal ensembles to assess their role in drug-related memories and behavior.
Interactions
c-Fos has been shown to
- BCL3,[34]
- COBRA1,[35]
- CSNK2A1,[36]
- CSNK2A2,[36]
- DDIT3,[37]
- NCOA1;,[45][46]
- NCOR2,[47]
- RELA,[38]
- RUNX1,[48][49]
- RUNX2,[48][49]
- SMAD3,[50] and
- TBP.[51]
See also
- Leptomycin
- c-Jun
- Egr-1
References
- G proteins & linked receptors(Text color) Transcription factors
- ^ a b c GRCh38: Ensembl release 89: ENSG00000170345 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021250 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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
- PMID 16199154.
- S2CID 43078284.
- PMID 26303532.
- S2CID 19876513.
- PMID 8039503.
- PMID 8058317.
- PMID 12197835.
- PMID 9873060.
- PMID 10963134.
- PMID 8601589.
- ^ PMID 19877494.
[Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events - PMID 22200950.
Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
- ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
- PMID 24939695.
- ^ PMID 21989194.
ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression - ^ 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 ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
- PMID 18640924.
Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
- PMID 18854825.
- PMID 2118661.
- S2CID 6727581.
- PMID 11927188.
- ^ S2CID 29821546.
- PMID 36992795.
- PMID 19050162.
- S2CID 3804201.
- PMID 18634767.
- PMID 19620976.
- PMID 22442487.
- PMID 10497212.
- PMID 15530430.
- ^ PMID 9685505.
- PMID 10523647.
- ^ PMID 10488148.
- PMID 11053448.
- PMID 9160889.
- S2CID 4276971.
- PMID 8440710.
- PMID 8380166.
- PMID 9872330.
- PMID 10847592.
- PMID 9642216.
- PMID 10777532.
- ^ PMID 11274169.
- ^ PMID 11641401.
- S2CID 4393852.
- PMID 8065335.
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. PMID 7962462.
- Pompeiano M, Cirelli C, Arrighi P, Tononi G (1995). "c-Fos expression during wakefulness and sleep". Neurophysiol Clin. 25 (6): 329–41. S2CID 23760149.
- Herrera DG, Robertson HA (October 1996). "Activation of c-fos in the brain". Prog. Neurobiol. 50 (2–3): 83–107. S2CID 31105978.
- 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. PMID 12183893.
External links
- c-fos+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- c-fos+Genes at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook c-Fos
- Drosophila kayak - The Interactive Fly
- Human FOS genome location and FOS gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P01100 (Human Proto-oncogene c-Fos) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: P01101 (Mouse Proto-oncogene c-Fos) at the PDBe-KB.