Fos-related antigen


Fos transcriptional targets

Rel/NF-kappaB transcription factors and IkappaBalpha (Drosophila homolog: Cactus) function in an autoregulatory network. Avian IkappaBalpha transcription is increased in response to both c-Rel and v-Rel. IkappaBalpha transcription is synergistically stimulated by Rel (Drosophila homolog: Dorsal) and AP-1 factors (c-Fos and c-Jun). A 386 bp region of the IkappaBalpha promoter (containing two NF-kappaB and one AP-1 binding sites) is necessary and sufficient for response to both Rel factors alone or Rel factors in conjunction with the AP-1 proteins. In addition, an imperfect NF-kappaB binding site is found to overlap the AP-1 binding site. Mutation of either of the NF-kappaB binding sites or the AP-1 binding site dramatically decreases the response of the IkappaBalpha promoter to Rel proteins alone or Rel and AP-1 factors. Overexpression of c-Rel results in the formation of DNA binding complexes associated with the imperfect NF-kappaB binding site that overlaps the AP-1 site. v-Rel has a stronger association with the imperfect NF-kappaB site than does c-Rel, and overexpression of v-Rel also results in the formation of a v-Rel containing complex bound to a consensus AP-1 site (Kralova, 1996).

Activation of the AP-1 transcription factor and TGF-beta1 growth factor by ionizing radiation was studied both in vivo in pig skin, and in vitro in human fibroblasts and keratinocytes. Three and 6 h after irradiation, the Fos and Jun proteins and their binding activity to an AP-1 consensus sequence are strongly induced by high doses of gamma-rays. c-Fos, c-Jun and JunB proteins are found to be present in gel-shift complexes by probing with specific antibodies. Both keratinocytes and fibroblasts exhibit heightened AP-1 activity following irradiation. Two and 6 h after irradiation, the levels of TGF-beta1 transcripts are increased in skin. By immunostaining, TGF-beta1 protein levels are found to be increased in fibroblasts, keratinocytes and endothelial cells. As the TGF-beta1 promoter contains AP-1 binding sites, the relation between AP-1 activity and TGF-beta1 induction was addressed. The -365 TGF-beta1 promoter fragment, which contains a high affinity AP-1 site, exhibits increased binding to Jun and Fos proteins following irradiation. These results suggest that stress-inducible TGF-beta1 expression is mediated by the activation of AP-1 transcription factor (Martin, 1997).

Transcriptional regulation by transforming growth factor beta (TGF-beta) is a complex process which is likely to involve cross talk between different DNA responsive elements and transcription factors to achieve maximal promoter activation and specificity. This work has uncovered a concurrent requirement for two discrete responsive elements in the regulation of the c-Jun promoter: one, a binding site for a Smad3-Smad4 complex and the other an AP-1 binding site. The two elements are located 120 bp apart in the proximal c-Jun promoter, and each is able to independently bind its corresponding transcription factor complex. The effects of independently mutating each of these elements are nonadditive; disruption of either sequence results in complete or severe reductions in TGF-beta responsiveness. This simultaneous requirement for two distinct and independent DNA binding elements suggests that Smad and AP-1 complexes function synergistically to mediate TGF-beta-induced transcriptional activation of the c-Jun promoter (Wong, 1999).

Expression of the fos family of transcription factors is stimulated by growth factors that induce quiescent cells to reenter the cell cycle, but the cellular targets of the Fos family that regulate cell cycle reentry have not been identified. To address this issue, mice that lack two members of the fos family, c-fos and fosB, were derived. The fosB-/- c-fos-/- mice are similar in phenotype to c-fos-/- mice but are 30% smaller. This decrease in size is consistent with an abnormality in cell proliferation. Fibroblasts derived from fosB-/- c-fos-/- mice have a defect in proliferation that results at least in part from a failure to induce cyclin D1 following serum-stimulated cell cycle reentry. Although definitive evidence that c-Fos and FosB directly induce cyclin D1 transcription will require further analysis, these findings raise the possibility that c-Fos and FosB are either direct or indirect transcriptional regulators of the cyclin D1 gene and may function as a critical link between serum stimulation and cell cycle progression (Brown, 1998).

Smad proteins transduce signals for transforming growth factor-beta (TGF-beta)-related factors. Smad proteins activated by receptors for TGF-beta form complexes with Smad4. These complexes are translocated into the nucleus and regulate ligand-induced gene transcription. 12-O-tetradecanoyl-13-acetate (TPA)-responsive gene promoter elements (TREs) are involved in the transcriptional responses of several genes to TGF-beta. AP-1 transcription factors, composed of c-Jun and c-Fos, bind to and direct transcription from TREs, which are therefore known as AP1-binding sites. Smad3 interacts directly with the TRE and Smad3 and Smad4 can activate TGF-beta-inducible transcription from the TRE in the absence of c-Jun and c-Fos. Smad3 and Smad4 also act together with c-Jun and c-Fos to activate transcription in response to TGF-beta, through a TGF-beta-inducible association of c-Jun with Smad3 and an interaction of Smad3 and c-Fos. These interactions complement interactions between c-Jun and c-Fos, and between Smad3 and Smad4. This mechanism of transcriptional activation by TGF-beta, through functional and physical interactions between Smad3-Smad4 and c-Jun-c-Fos, shows that Smad signaling and MAPK/JNK signaling converge at AP1-binding promoter sites (Zhang, 1998).

Activation of helper T cells results in coordinate expression of a number of cytokines involved in differentiation, proliferation and activation of the hematopoietic system. Granulocyte-macrophage colony stimulating factor (GM-CSF) is one such cytokine, whose increased expression results mostly from increases in transcription. Cis-acting elements with NFkappaB, AP1 and ETS-like binding motifs have been identified in the promoter region of the GM-CSF gene, and are important or essential for transcriptional activity following T cell activation. ETS1 is a transcription factor of the ETS family that is expressed in T cells. ETS1 can transactivate GM-CSF in Jurkat T cells, but only after the cells have been stimulated by treatment with PMA and ionomycin, agents that mimic T cell activation. ETS1, which is expressed constitutively in Jurkat cells, may act in concert with PMA/ionomycin inducible factors. ETS1 can transactivate a GM-CSF reporter construct in unstimulated Jurkat cells, providing that either NFkappaB or AP1 transcription factors are supplied by co-transfection. Binding of endogenous NFkappaB and AP1 is induced following PMA/ionomycin treatment of T cells. Transactivation by ETS1, NFkappaB and AP1 is synergistic, and mutation of the individual binding sites reveals that the transcriptional activities of these factors are interdependent. These results suggest that constitutive ETS1, and inducible NFkappaB and AP1, cooperate as part of a higher order transcriptional complex in activated T cells (Thomas, 1997).

Tissue factor (TF) is induced in THP-1 cells stimulated with lipopolysaccharide (LPS). DNase I footprinting identifies six sites of protein-DNA interaction between -383 and the cap site of the TF promoter that vary in the amounts of control and induced extracts. Four footprints show qualitative differences in nuclease sensitivity. Footprints I (-85 to -52) and V (-197 to -175) are induction-specific and localize to regions of the promoter that mediate serum, phorbol ester, partial LPS response (-111 to +14), and the major LPS-inducible element (-231 to -172). Electrophoretic mobility shift assays with the -231 to -172 probe demonstrate JunD and Fos binding in both control and induced nuclear extracts; however, binding of c-Jun is only detected following LPS stimulation. Antibody inhibition studies implicate binding of Ets-1 or Ets-2 to the consensus site between -192 and -177, a region that contains an induction-specific footprint. The proximal region (-85 to -52), containing the second inducible footprint, binds Egr-1 following induction. These data suggest that LPS stimulation of THP-1 cells activate binding of c-Jun, Ets, and Egr-1 to the TF promoter and implicates these factors in the transcriptional activation of TF mRNA synthesis (Groupp, 1997).

Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the Rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, a MAPK-ERK kinase (MEK) inhibitor has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit (Newberry, 1997).

Osteocalcin (OC), a bone specific protein expressed during differentiation and mineralization of the bone extracellular matrix, is down-regulated upon treatment with transforming growth factor (TGF)-beta 1. To address the potential role of OC gene expression in relation to TGF-beta 1 regulation of bone formation and resorption, the transcriptional activity of the rat OC promoter was studied after TGF-beta 1 treatment. 5' deletion analysis of rat OC promoter-chloramphenicol acetyltransferase constructs demonstrate that TGF-beta 1 treatment represses chloramphenicol acetyltransferase activity by 2.4-fold in transient transfections of ROS 17/2.8 cells. A 29-bp region between -162 and -134 identified as the TGF-beta 1 response domain, confers TGF-beta 1 responsiveness to the -108 to +24 rat OC basal promoter in an orientation dependent manner. Mutation of an activator protein-1/cAMP-response element-like motif (- 146 to -139) abolishes TGF-beta 1 responsiveness of the construct. Fra-2, a Fos related transcription factor, binds to this motif as indicated by an in vitro gel-mobility shift and competition assays using wild-type and mutated oligonucleotides and antibodies. Fra-2 is an activator of the OC promoter; TGF-beta 1 inhibits this activation. These results demonstrate that Fra-2 is hyperphosphorylated upon TGF-beta 1 treatment of ROS 17/2.8 cells. Treatment of cells with a staurosporine protein kinase C inhibitor abrogates TGF-beta 1 mediated down-regulation of the OC promoter activity. Together, these results demonstrate that TGF-beta 1 responsiveness of the rat osteocalcin gene in ROS 17/2.8 cells is mediated through an activator protein-1 like cis-acting element that interacts with Fra-2. These results are consistent with a critical role for TGF-beta 1 induced phosphorylation of Fra-2 in the repression of OC gene transcription (Banerjee, 1996).

In bovine chromaffin cells, either forskolin, phorbol ester, or high potassium levels induce a rapid increase of c-fos, c-jun, and junB mRNA levels, which precede an induction of proenkephalin gene expression. Preincubation of the cells with cycloheximide inhibits induction of proenkephalin mRNA levels by each of these agents, indicating that newly synthesized transcription factors are involved. Transient transfection of reporter genes show that the ENKCRE-2 element of the proenkephalin promoter is sufficient for basal and second messenger-induced expression. Stimulation increases the binding of nuclear proteins to ENKCRE-2 and AP-1 oligonucleotides but not to CRE oligonucleotides. The induction of AP-1 binding activity is associated with Fos protein synthesis. Cotransfection of c-fos, but neither of c-jun nor CREB expression plasmids, transactivates the expression of the PENKCAT reporter genes. These results suggest that Fos and/or other components of AP-1 transcription factors, rather than CREB or other preexisting proteins, play a specific role in the induction of the proenkephalin gene in bovine chromaffin cells (Bacher, 1996).

Cooperation between nuclear factor of activated T cells (NFAT: Drosophila homolog: CG11172) and AP-1 (Fos-Jun) proteins on composite NFAT-AP-1 DNA elements constitutes a powerful mechanism for signal integration of the calcium and protein kinase C/Ras pathways in the regulation of gene expression. NFAT can induce expression of certain genes in T cells without the need for cooperative recruitment of Fos and Jun. Using NFAT1 mutant proteins that are unable to interact with Fos-Jun dimers but are unaffected in DNA binding or transcriptional activity, it has been shown that expression of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-4, MIP1alpha and Fas ligand mRNAs are all absolutely dependent on cooperation between NFAT and Fos-Jun; in contrast, NFAT induces tumor necrosis factor alpha mRNA and IL-13 promoter activity without any necessity to recruit Fos and Jun. Furthermore, NFAT-Fos-Jun cooperation is also essential to elicit the NFAT-dependent program of activation-induced cell death. These results support the hypothesis that even in a single cell type, NFAT activation can evoke two distinct biological programs of gene expression, dependent or independent of NFAT-AP-1 cooperation (Macian, 2000).

Early developmental role for Fos

Fra1 is an immediate-early gene encoding a member of the AP-1 transcription factor family, which has diverse roles in development and oncogenesis. To determine the function of Fra1 in mouse development, the gene was inactivated by gene targeting. Fetuses lacking Fra1 are severely growth retarded and die between E10.0 and E10.5, owing to defects in extra-embryonic tissues. The placental labyrinth layer, where X-gal staining revealed expression of Fra1, is reduced in size and largely avascular, owing to a marked decrease in the number of vascular endothelial cells, as shown by the lack of Flk1 expression. In contrast, the spongiotrophoblast layer is unaffected and expresses the marker genes 4311(Tpbp) and Flt1. Furthermore, mutant fetuses exhibit yolk-sac defects that may contribute to their growth retardation and lethality. Importantly, when the placental defect is rescued by injection of Fra1-/- ES cells into tetraploid wild-type blastocysts, Fra1-/- pups are obtained that are no longer growth retarded and survive up to 2 days after birth without apparent phenotypic defects. These data indicate that a defect in the extra-embryonic compartment is causal to the observed lethality, and suggest that Fra1 plays a crucial role in establishing normal vascularisation of the placenta (Schreiber, 2000).

M-phase promoting factor is a complex of cdc2 and cyclin B that is regulated positively by cdc25 phosphatase and negatively by wee1 kinase. The wee1 gene promoter has been isolated and is found to contain one AP-1 binding motif and is directly activated by the immediate early gene product c-Fos at cellular G1/S phase. In antigen-specific Th1 cells stimulated by antigen, transactivation of the c-fos and wee1 kinase genes occurs sequentially at G1/S, and the substrate of wee1 kinase, cdc2-Tyr15, is subsequently phosphorylated at late G1/S. Under prolonged expression of the c-fos gene, however, the amount of wee1 kinase is increased and its target cdc2 molecule is constitutively phosphorylated on its tyrosine residue. Th1 cells consequently go into aberrant mitosis. Thus, an immediate early gene product, c-Fos/AP-1, directly transactivates the wee1 kinase gene at G1/S. The transient increase in c-fos and wee1 kinase genes is likely to be responsible for preventing premature mitosis while the cells remain in the G1/S phase of the cell cycle (Kawasaki, 2001).

The function of heterodimeric AP-1 comprised of c-Jun and c-Fos in activin mediated Spemann organizer gene expression

Activator protein-1 (AP-1) is a mediator of BMP or FGF signaling during Xenopus embryogenesis. However, specific role of AP-1 in activin signaling has not been elucidated during vertebrate development. This study provides new evidence showing that overexpression of heterodimeric AP-1 comprised of c-jun and c-fos [AP-1(c-Jun/c-Fos)] induces the expression of BMP-antagonizing organizer genes (noggin, chordin and goosecoid) that were normally expressed by high dose of activin. AP-1(c-Jun/c-Fos) enhanced the promoter activities of organizer genes but reduced that of PV.1, a BMP4-response gene. A loss of function study clearly demonstrated that AP-1(c-Jun/c-Fos) is required for the activin-induced organizer and neural gene expression. Moreover, physical interaction of AP-1(c-Jun/c-Fos) and Smad3 cooperatively enhanced the transcriptional activity of goosecoid via direct binding on this promoter. Interestingly, Smad3 mutants at c-Jun binding site failed in regulation of organizer genes, indicating that these physical interactions are specifically necessary for the expression of organizer genes. In is concluded that AP-1(c-Jun/c-Fos) plays a specific role in organizer gene expression downstream of activin signal during early Xenopus embryogenesis (Lee, 2011).

Dimeric combinations of MafB, cFos and cJun control the apoptosis-survival balance in limb morphogenesis

Apoptosis is an important mechanism for sculpting morphology. However, the molecular cascades that control apoptosis in developing limb buds remain largely unclear. This study showed that bZip factor MafB was specifically expressed in apoptotic regions of chick limb buds, and MafB/cFos heterodimers repressed apoptosis, whereas MafB/cJun heterodimers promoted apoptosis for sculpting the shape of the limbs. Chromatin immunoprecipitation sequencing in chick limb buds identified potential target genes and regulatory elements controlled by Maf and Jun. Functional analyses revealed that expression of p63 and p73, key components known to arrest the cell cycle, was directly activated by MafB and cJun. The data suggest that dimeric combinations of MafB, cFos and cJun in developing chick limb buds control the number of apoptotic cells, and that MafB/cJun heterodimers lead to apoptosis via activation of p63 and p73 (Suda, 2014).

Fos activation in neurons

To determine if muscarinic receptor-activation plays a role in oligodendrocyte development, the effect of carbachol, a stable acetylcholine analog, on gene expression and proliferation was investigated. Carbachol causes a time and concentration-dependent increase in c-fos mRNA. This effect is blocked by atropine, a non-selective muscarinic antagonist. the muscarinic-stimulated c-fos increase is inhibited by a potent inhibitor of protein kinase C (PKC), but not by a potent inhibitor of protein kinase A, suggesting the involvement of PKC in mediating the response. Down-regulation of PKC by overnight pre-treatment with phorbol ester blocks only the phorbol ester-stimulated c-fos accumulation, while no effect is observed in the carbachol-induced response. These results suggest that carbachol stimulates a PKC pathway that may be different from that activated by phorbol. Further evidence for two separate mechanisms of proto-oncogene induction is provided by the additive effect of carbachol and phorbol. Induction of c-fos mRNA by carbachol is dependent on both influx of extracellular Ca2+ and release from intracellular stores, as both EDTA and BAPTA block the response. Since activation of muscarinic receptors can affect cell division in other cellular systems, the effect of carbachol on [3H]thymidine and bromodeoxyuridine incorporation into oligodendrocyte DNA was measured. Carbachol stimulates DNA synthesis in oligodendrocyte progenitors. This effect is mediated by muscarinic receptors, since [3H]thymidine incorporation is prevented or significantly reduced by the addition of atropine. In conclusion, the present findings suggest that, the neurotransmitter, acetylcholine may act as a trophic factor in developing oligodendrocytes, regulating their growth and development in the central nervous system (Cohen, 1997).

The neurotransmitter glutamate stimulates rapid and transient induction of many genes, including the c-fos proto-oncogene. The c-fos promoter contains several critical regulatory elements, including the serum response element (SRE) that mediate glutamate-induced transcription in neurons. To facilitate the analysis of fos induction in cortical neurons, an improved calcium phosphate coprecipitation procedure was developed to transiently introduce DNA into primary neurons. Using this protocol, it has been demonstrated that the transcription factors serum response factor (SRF) and Elk-1 can mediate glutamate induction of transcription through the SRE in cortical neurons. There are at least two distinct pathways by which glutamate signals through the SRE: an SRF-dependent pathway that can operate in the absence of Elk and an Elk-dependent pathway. Activation of the Elk-dependent pathway of transcription seems to require phosphorylation of Elk-1 by extracellular signal-regulated kinases (ERKs), providing evidence of a physiological function for ERKs in glutamate signaling in neurons. Taken together, these findings suggest that SRF, Elk, and ERKs may have important roles in neuroplasticity (Xia, 1996).

Numerous in vivo studies have demonstrated that psychostimulant drugs such as amphetamine and cocaine can induce the expression of the immediate early gene c-fos in striatal neurons via the activation of D1 dopamine receptors. NMDA receptor activation is also known to induce c-fos in the striatum. A primary striatal neuronal culture preparation was used to examine the mechanisms whereby these stimuli lead to changes in gene expression. Direct application of NMDA to striatal cells in culture causes a rapid increase in the expression of c-fos as well as an increase in the phosphorylation of the transcription factor CRE binding protein (CREB). This is prevented by NMDA receptor antagonists, and requires extracellular calcium, but does not involve L-type calcium channels. The response to NMDA was blocked by KN62, a selective inhibitor of calcium/calmodulin-dependent protein kinase. Application of a D1 agonist, or direct stimulation of adenylyl cyclase with forskolin, also results in the phosphorylation of CREB and the induction of c-fos in striatal neurons. These effects are blocked by a protein kinase A inhibitor. These observations are consistent with the hypothesis that calcium/calmodulin-dependent phosphorylation of CREB, induced by NMDA, or cAMP-dependent phosphorylation of CREB, induced by D1 agonists, underlie the induction of c-fos seen following the activation of these receptors in striatal neurons (Das, 1997).

The AP-1 family of transcription factors has been implicated in the control of the expression of many genes in response to environmental signals. Previous studies have provided temporal profiles for c-fos expression by taking measurements from many animals at several points in time, but these studies provide limited information about dynamic changes in expression. A method has been devised of continuously measuring c-fos expression. A transgenic mouse line expressing the human c-fos promoter linked to the firefly luciferase reporter gene (fos/luc) was generated to continuously monitor c-fos gene expression. A second transgenic mouse line expressing luciferase under the control of the cytomegalovirus promoter (CMV/luc) served as a control. Luminescence originating from identifiable brain regions was imaged from fos/luc brain slice cultures. Expression of the fos/luc transgene accurately reflects transcriptional responses of the endogenous c-fos gene. Dynamic changes in fos/luc expression in suprachiasmatic nuclei (SCN) explant cultures were monitored continuously; luminescence shows an almost 24 hour rhythm pattern lasting up to five circadian cycles. In contrast, bioluminescence monitored from CMV/luc SCN explant cultures is not rhythmic. It is concluded that the fos/luc transgenic mouse will be useful for long-term, non-invasive monitoring of c-fos transcriptional responses to the changing cellular environment. Circadian rhythms in c-fos expression can be monitored non-invasively in real time from the SCN, clearly demonstrating that c-fos transcription is regulated by the circadian clock (Geusz, 1997).

Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. Long-lasting Fos-related proteins of 35-37 kDa are induced in the striatum by chronic cocaine administration. The striatum of fosB mutant mice completely lacks basal levels of the 35- to 37-kDa Fos-related proteins as well as their induction by chronic cocaine administration. This deficiency is associated with enhanced behavioral responses to cocaine: fosB mutant mice show exaggerated locomotor activation in response to initial cocaine exposures as well as robust conditioned place preference to a lower dose of cocaine, compared with wild-type littermates. These results establish the long-lasting Fos-related proteins as products of the fosB gene (specifically DeltaFosB isoforms) and suggest that transcriptional regulation by fosB gene products plays a critical role in cocaine-induced behavioral responses. This finding demonstrates that a Fos family member protein plays a functional role in behavioral responses to drugs of abuse and implicates fosB gene products as important determinants of cocaine abuse (Hiroi, 1997).

Acute suppression, but not chronic genetic deficiency, of c-fos gene expression impairs long-term memory in aversive taste learning

Several lines of evidence have indicated that the establishment of long-term memory requires protein synthesis, including the synthesis of immediate-early gene products. Although the anatomical expression patterns of the c-fos gene, a transcription factor-encoding immediate-early gene, in conditioned taste aversion (CTA) are well documented, the functional roles of c-fos gene expression and Fos-mediated transcription remain to be clarified. Using the antisense oligodeoxynucleotide (AS-ODN) method in rats and gene-targeting knockout techniques in mice (c-fos-/- mice), the roles of c-fos gene expression in the acquisition, retrieval, and retention of CTA were examined. Preconditioning microinfusion of AS-ODN directed against c-fos mRNA (c-fos AS-ODN) into the parabrachial nucleus (PBN) impaired the acquisition. Microinfusion of c-fos AS-ODN into either the amygdala or insular cortex did not impair the acquisition, whereas it attenuated the retention. Retrieval and subsequent retention of an acquired CTA were not disrupted by c-fos AS-ODN infusion into the PBN or amygdala. Microinfusion of another AS-ODN directed against zif268 (egr-1, krox-24, NGFI-A) mRNA into the PBN or amygdala did not affect the acquisition and retention. The genetic deficiency in c-fos-/- mice caused normal acquisition and retention. The present results suggest that the Fos-mediated gene transcription in the PBN, amygdala, or insular cortex plays critical roles in the acquisition and/or consolidation, but not the retrieval, of long-term taste memory; nevertheless, some other factors could compensate CTA mechanism when Fos-mediated transcription is not available (Yasoshima, 2006).

Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding

Ligand-dependent transcription by the nuclear receptor glucocorticoid receptor (GR) is mediated by interactions with coregulators. The role of these interactions in determining selective binding of GR to regulatory elements remains unclear. Recent findings indicate that a large fraction of genomic GR binding coincides with chromatin that is accessible prior to hormone treatment, suggesting that receptor binding is dictated by proteins that maintain chromatin in an open state. Combining DNaseI accessibility and chromatin immunoprecipitation with high-throughput sequencing, the activator protein 1 (AP1) was identified as a major partner for productive GR-chromatin interactions. AP1 is critical for GR-regulated transcription and recruitment to co-occupied regulatory elements, illustrating an extensive AP1-GR interaction network. Importantly, the maintenance of baseline chromatin accessibility facilitates GR recruitment and is dependent on AP1 binding. A model is proposed in which the basal occupancy of transcription factors acts to prime chromatin and direct inducible transcription factors to select regions in the genome (Biddie, 2011).

Fos and cartilage development

The Fos-related AP1 transcription factor Fra2 (encoded by Fosl2) is expressed in various epithelial cells as well as in cartilaginous structures. The role was studied of Fra2 in cartilage development. The absence of Fra2 in embryos and newborns leads to reduced zones of hypertrophic chondrocytes and impaired matrix deposition in femoral and tibial growth plates, probably owing to impaired differentiation into hypertrophic chondrocytes. In addition, hypertrophic differentiation and ossification of primordial arches of the developing vertebrae are delayed in Fra2-deficient embryos. Primary Fosl2–/– chondrocytes exhibit decreased hypertrophic differentiation and remain in a proliferative state longer than wild-type cells. Since pups lacking Fra2 die shortly after birth, mice carrying `floxed' Fosl2 alleles were generated and crossed to coll2a1-Cre mice, allowing investigation of postnatal cartilage development. The coll2a1-Cre, Fosl2f/f mice die between 10 and 25 days after birth, are growth retarded and display smaller growth plates similar to Fosl2–/– embryos. In addition, these mice suffer from a kyphosis-like phenotype, an abnormal bending of the spine. Hence, Fra2 is a novel transcription factor important for skeletogenesis by affecting chondrocyte differentiation (Karreth, 2004).

Fos and heart disease

Cardiac hypertrophic stimuli induce both adaptive and maladaptive growth response pathways in the heart. Mice lacking junD develop less adaptive hypertrophy in the heart after mechanical pressure overload, while cardiomyocyte-specific expression of junD in mice results in spontaneous ventricular dilation and decreased contractility. In contrast, fra-1 conditional knock-out mice have a normal hypertrophic response, whereas hearts from fra-1 transgenic mice decompensate prematurely. Moreover, fra-1 transgenic mice simultaneously lacking junD reveal a spontaneous dilated cardiomyopathy associated with increased cardiomyocyte apoptosis and a primary mitochondrial defect. These data suggest that junD promotes both adaptive-protective and maladaptive hypertrophy in heart, depending on its expression levels (Ricci, 2005).

Fos and oncogenesis

The Finkel-Biskis-Jinkins murine sarcoma virus, which carries v-fos, induces osteosarcomas, whereas high-level expression of exogenous c-fos in transgenic and chimeric mice leads to postnatal development of osteogenic and chondrogenic tumors, respectively. To test whether such target cell specificity of an oncogene can be detected even in early development, ectopic expression of fos was induced in chicken limb buds by microinjecting replication-competent retrovirus into the presumptive leg field of stage 10 embryos. This causes cartilage truncation of all the long bones of the injected leg, which is mainly attributable to chondrodysplasia due to severe retardation of differentiation of the proliferating chondrocytes into mature or hypertrophic chondrocytes, as well as a slight delay in precartilagenous condensation. Expression of genes for all the other known members of chicken AP-1, which include such transforming genes as c-jun and fra-2, however, causes no macroscopic abnormalities in limb formation, indicating a specific function of Fos proteins in embryonic endochondral bone differentiation. The extent of truncation is stronger with v-Fos than with c-Fos; comparative analysis of these proteins, as well as v-Fos mutants, reveals that strong transforming activity of Fos protein is necessary to cause dysplasia, suggesting that common molecular mechanisms are involved in both embryonic chondrodysplasia and bone tumor formation in postnatal mice (Watanabe, 1997).

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Fos-related antigen: Biological Overview | Regulation | Developmental Biology | Effects of Mutation | References

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