c-Fos

FBJ murine osteosarcoma viral oncogene homolog
Structure of NFAT(green), Jun(blue) and Fos(red) bound to DNA. Based on PDB entry 1a02.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1A02, 1FOS, 1S9K
Identifiers
Symbols	FOS ; AP-1; C-FOS; p55
External IDs	OMIM: 164810 MGI: 95574 HomoloGene: 3844 ChEMBL: 5029 GeneCards: FOS Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II core promoter sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • chromatin binding • double-stranded DNA binding • transcription factor activity, sequence-specific DNA binding • protein binding • transcription factor binding • transcription regulatory region DNA binding • R-SMAD binding Cellular component • nucleus • nucleoplasm • transcription factor complex • endoplasmic reticulum • cytosol • membrane • neuron projection Biological process • conditioned taste aversion • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • DNA methylation • regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • inflammatory response • transforming growth factor beta receptor signaling pathway • nervous system development • female pregnancy • aging • response to cold • response to light stimulus • response to gravity • response to toxic substance • sleep • cellular response to extracellular stimulus • response to lipopolysaccharide • response to progesterone • cellular response to hormone stimulus • response to cytokine • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • toll-like receptor 5 signaling pathway • toll-like receptor 9 signaling pathway • toll-like receptor 10 signaling pathway • cellular response to reactive oxygen species • TRIF-dependent toll-like receptor signaling pathway • response to immobilization stress • skeletal muscle cell differentiation • response to muscle stretch • Fc-epsilon receptor signaling pathway • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • response to drug • innate immune response • positive regulation of osteoclast differentiation • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • regulation of sequence-specific DNA binding transcription factor activity • stress-activated MAPK cascade • response to corticosterone • response to cAMP • SMAD protein signal transduction • cellular response to calcium ion Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2353	14281
Ensembl	ENSG00000170345	ENSMUSG00000021250
UniProt	P01100	P01101
RefSeq (mRNA)	NM_005252	NM_010234
RefSeq (protein)	NP_005243	NP_034364
Location (UCSC)	Chr 14: 75.28 – 75.28 Mb	Chr 12: 85.47 – 85.48 Mb
PubMed search	[1]	[2]

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. 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. 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. 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 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.

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. 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. 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; 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.

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 pore

Nuclear membrane

Plasma membrane

Ca_v1.2

NMDAR

AMPAR

DRD1

DRD5

DRD2

DRD3

DRD4

G_s

G_i/o

cAMP

cAMP

PKA

CaM

CaMKII

DARPP-32

PP1

PP2B

CREB

ΔFosB

JunD

c-Fos

SIRT1

HDAC1

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, postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation. Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors; c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron. A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated high-dose exposure to stimulants through this process. 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.

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.

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, heroin, and other psychoactive drugs 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.

Applications

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

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. This neuronal control can be replicated with optogenetics or DREADDs

Interactions

C-Fos has been shown to interact with:

• BCL3,
• COBRA1,
• CSNK2A1,
• CSNK2A2,
• DDIT3,
• JUN
• NCOA1;,
• NCOR2,
• RELA,
• RUNX1,
• RUNX2,
• SMAD3, and
• TBP.

See also

• Leptomycin
• c-Jun
• Egr-1

External links

• c-fos Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
• c-fos Genes at the US National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook C-Fos
• Drosophila kayak - The Interactive Fly