Protein c-Fos

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C-Fos
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FOS
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_005252

NM_010234

RefSeq (protein)

NP_005243
NP_005243.1

NP_034364

Location (UCSC)Chr 14: 75.28 – 75.28 MbChr 12: 85.52 – 85.52 Mb
PubMed search[3][4]
Wikidata
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Protein c-Fos is a

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.[7]
It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

Structure and function

c-Fos is a 380 amino acid protein with a basic

homodimers.[8] In vitro studies have shown that Jun–Fos heterodimers are more stable and have stronger DNA-binding activity than Jun–Jun homodimers.[9]

A variety of stimuli, including

MAPK, CDC2, PKA or PKC which influence protein stability, DNA-binding activity and the trans-activating potential of the transcription factors.[11][12][13]
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

epithelial-mesenchymal transition, leading to invasive and metastatic growth in mammary epithelial cells.[15]

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
Note: colored text contains article links.
Nuclear membrane
Plasma membrane
Cav1.2
DARPP-32
PP2B
CREB
ΔFosB
c-Fos
HDAC1
The image above contains clickable links
This diagram depicts the signaling events in the
nuclear factor kappa B), it induces an addictive state.[20][21]

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,

acts as a molecular switch that enables the chronic induction of ΔFosB, thus allowing it to accumulate more rapidly. 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.[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.

DREADDs.[33]

Mixed neural cultures derived from rat embryos were grown under normal conditions (left) or treated with 55mM Potassium for 5 hours (right). Cultures were then stained with antibody to the intermediate filament protein vimentin (green), antibody to cFos (red) and with a DNA binding dye (blue). The vimentin antibody reveals non-neuronal cells and the DNA dye shows the nuclei of all cells. The potassium treatment depolarizes the neurons and induces strong expression of cFos in neuronal cell bodies as shown in the right image. Cell culture, Image and antibody generation all performed in the EnCor Biotechnology laboratory.

Interactions

c-Fos has been shown to

interact
with:

See also

References

  1. G proteins & linked receptors
      (Text color) Transcription factors
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000170345 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021250 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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
  6. PMID 16199154
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    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
  17. . 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.
  18. ^ 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.
  19. PMID 24939695
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    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
  21. ^ . 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
  22. . 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
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Further reading

External links

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