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PubMed1992

Opposing actions of Fos and Jun on transcription of the phosphoenolpyruvate carboxykinase (GTP) gene. Dominant negative regulation by Fos.

Jun homodimers and Fos/Jun heterodimers bind to the gene for phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) at three sites within the first 350 base pairs of the promoter. These include CRE-1 (-82 to -90), and P3(II) and P4 (-252 to -258 and -268 to -285, respectively). Over-expression of Jun in HepG2 cells resulted in a 10-15-fold increase in the level of transcription of a chimeric PEPCK (-490 to +73)-CAT gene, while expression of Fos decreased transcription and blocked the induction of transcription from the PEPCK promoter by Jun. The action of Fos and Jun on PEPCK gene transcription involved each of the Fos/Jun-binding sites and was modulated by additional transcriptional regulatory elements within the PEPCK promoter. The ability of Fos to inhibit PEPCK transcription was dependent upon P3(I), a region of the promoter which does not bind Fos/Jun heterodimers, but does bind members of the C/EBP family of transcription factors. Stimulation of PEPCK transcription by 8-Br-cAMP or by overexpression of the catalytic subunit of protein kinase A was inhibited by Fos expression. The inhibitory effects of phorbol esters and protein kinase C on PEPCK gene expression may be mediated through the action of Fos and Jun.

Binding Sites↗
PubMed1994

Directionally specific changes in arterial pressure induce differential patterns of fos expression in discrete areas of the rat brainstem: a double-labeling study for Fos and catecholamines.

Although the nucleus tractus solitarii (NTS) has been established as the primary site of synaptic integration for the baroreceptor reflex, the higher-order pathways responsive to, and mediating, changes in vasomotor tone are not well characterized. We used immunohistochemistry to determine the distribution of cells expressing the Fos protein following pharmacologically induced, directionally specific changes in arterial pressure. The goal of this investigation was to determine if this immediate early gene product is differentially expressed in neurons of the rat brainstem following increased (pressor) versus decreased (depressor) arterial blood pressure (AP). Because brainstem catecholaminergic (CA) cell groups have been implicated in cardiovascular regulation, a double-labeling immunohistochemical procedure was used to examine the distribution of Fos in CA cells. Animals received continuous intravenous infusion of either a vasoconstrictor (l-phenylephrine hydrochloride), a vasodilator (sodium nitroprusside), or physiological saline. Extensive Fos-like immunoreactivity (FLI) was induced in both the pressor and depressor conditions in the NTS, caudal ventrolateral medulla (CVLM), rostral ventrolateral medulla (RVLM), A5, locus coeruleus (LC), Kolliker-Fuse, and parabrachial nucleus (PBN). These regions have all been implicated in central cardiovascular regulation. There were differences in the anatomical distribution of Fos-positive cells along the rostrocaudal axis of CVLM in the pressor and depressor conditions. Specifically, increased AP induced significantly more FLI cells within the rostral aspects of CVLM, whereas decreased AP resulted in a significantly greater number of FLI cells within the caudal CVLM. This result suggests that selective vasomotor responses differentially engaged discrete subsets of neurons within this brainstem region. Overall, approximately 50% of CA-immunoreactive cells were also FLI (CA-FLI) in the A1, A5, and A7 regions. Interestingly, increased AP produced significantly more CA-FLI double-labeled cells within the caudal than rostral A1 compared with depressor and control groups. Additionally, increased AP yielded significantly less CA-FLI double-labeled cells within the caudal A2 region. This suggests that CA barosensitive neurons in the CVLM/A1 and NTS/A2 regions are functionally segregated along the rostrocaudal axis of these structures. While twice as many PNMT-FLI double-labeled neurons were found in the C1-C3 regions following vasomotor changes versus saline control, there were no differences in the numbers or anatomical locations of labeled cells between pressor versus depressor groups. The results of this study indicate that (1) tonic changes in AP induce robust Fos expression in brainstem cardiovascular areas and (2) neurons responsive to specific directional changes in arterial pressure are segregated in some brainstem regions.

Animals↗
PubMed1994

Induction of Fos-like immunoreactivity (Fos-li) and stimulation of feeding by 2,5-anhydro-D-mannitol (2,5-AM) require the vagus nerve.

The antimetabolic fructose analogue, 2,5-anhydro-D-mannitol (2,5-AM), stimulates feeding. Selective hepatic branch vagotomy has been shown to block feeding induced by low 2,5-AM doses. However, hepatic vagal fibers are not the sole mediators of 2,5-AM-induced feeding, since hepatic branch vagotomy does not impair feeding induced by higher doses of 2,5-AM. To further evaluate the role of the vagus in the response to 2,5-AM, we examined the effect of total subdiaphragmatic vagotomy on feeding induced by a high 2,5-AM dose (500 mg/kg). In addition, we assessed the ability of 2,5-AM (300 and 500 mg/kg) to induce Fos-like immunoreactivity (Fos-li) in the brain in sham-operated (SHAM), hepatic branch vagotomized (HBV) and total subdiaphragmatic vagotomized (TSDV) rats. Both doses of 2,5-AM, but not control solutions, induced Fos-li in the area postrema (AP), nucleus of the solitary tract (NTS) and lateral parabrachial nucleus (1PBN). Very weak immunoreactivity was present in the central nucleus of the amygdala and none was observed in the locus coeruleus or paraventricular nucleus of the hypothalamus. The effect of the lower 2,5-AM dose on Fos-li was blocked by HBV. The high dose effect was blocked by TSDV but not by HBV. Feeding induced by the high dose of 2,5-AM was also blocked by TSDV. Results are consistent with the hypothesis that stimulation of feeding by 2,5-AM is dependent on the vagus nerve. Hepatic branch fibers may have the lowest threshold for activation, but fibers in other vagal branches independently mediate induction of c-fos and stimulate food intake at higher doses of the analogue.

Animals↗
PubMed1991

Fracture healing induces expression of the proto-oncogene c-fos in vivo. Possible involvement of the Fos protein in osteoblastic differentiation.

Here we report marked in vivo expression of the c-fos gene in the external soft callus (ESC) and periosteal hard callus (PHC) at the fracture site of adult rat tibia. Northern-blot analysis showed that the ESC expressed a high level of c-fos mRNA from post-fracture day 10 to day 28, the time when endochondral ossification progressed, and that the ossifying PHC also expressed c-fos mRNA. This c-fos expression was followed by sequential expression of the genes for alkaline phosphatase, osteopontin and osteocalcin, which are osteoblastic markers. Immunohistochemical analysis showed that the c-Fos protein was predominantly located in osteoblasts in the ossifying calluses.

Alkaline Phosphatase↗
PubMed1994

Circadian regulation of Fos B is different from c-Fos in the rat suprachiasmatic nucleus.

We measured immunoreactive Fos B protein levels in the ventrolateral subdivision of the rat suprachiasmatic nucleus (SCN) as a function of light and time of day. Immunohistochemistry revealed high levels of Fos B that were uniformly expressed throughout the 12 h:12 h light-dark cycle. Levels remained high in constant darkness and were modestly increased (about 2-fold) after a 2 h light pulse administered during the subjective night, but not after a light pulse during the subjective day. Fos B and c-Fos immunoreactivities could be colocalized within individual SCN cell nuclei using a double-label immunofluorescence method. Thus, despite their structural similarities, these two members of the fos gene family exhibit different patterns of expression in the rat SCN. These and previous data suggest that Fos/Jun DNA-binding complexes in the SCN are composed of constant, as well as variable, protein components; in at least some SCN cells, light-induced changes in the composition of these constituent proteins may lead to altered transcription of target genes.

Animals↗
PubMed1991

Co-expression of the proto-oncogene fos (c-fos) and an embryonic interferon (ovine trophoblastin) by sheep conceptuses during implantation.

Expression of the c-fos proto-oncogene by ovine conceptuses was analyzed by Northern and slot blots and indirect immunohistofluorescence in relation to the expression of the embryonic interferon-alpha (oTP) during implantation. c-fos was expressed initially in the trophoblast, and then in the allantois, when this tissue began to develop (day 17). In the embryonic tissues, the c-fos proto-oncogene was weakly expressed up to day 22 and increased thereafter. In the trophoblast, the expression of c-fos proto-oncogene was transient, occurring when the oTP gene was transcribed at a maximal level at the beginning of implantation (days 14-15), and decreased thereafter, following the pattern of oTP gene expression. This decline is due essentially to the arrest of c-fos and oTP gene expression by the trophoblastic cells which established cellular contacts with the uterine epithelium during the implantation process.

Actins↗
PubMed2005

Fast Fos: rapid protocols for single- and double-labeling c-Fos immunohistochemistry in fresh frozen brain sections.

Immunohistochemical localization of c-Fos immunoreactivity has been used successfully for over a decade to visualize patterns of neuronal activity in the brain and spinal cord. These experiments are extremely useful in identifying physiological or pharmacological activation of specific populations of neurons. Unfortunately, conventional c-Fos immunohistochemical protocols are very time and resource intensive. We have adapted and optimized established c-Fos immunohistochemistry (IHC) methodologies for use with fresh frozen brain tissue mounted directly onto slides. The resultant rapid protocols, which we refer to as "Fast Fos", include applications for single- and double-labeling, utilizing either enzyme-substrate or fluorescent detection systems. These protocols provide increased assay throughput and reproducibility, which can be further enhanced by use of an automated slide stainer. Taken as a whole, the c-Fos IHC protocols described in this report provide a flexible system for the identification of neuronal activation that substantially reduces time and resource expenditure while increasing quality and reproducibility of data.

Animals↗
PubMed1999

D-Fenfluramine induces serotonin-mediated Fos expression in corticotropin-releasing factor and oxytocin neurons of the hypothalamus, and serotonin-independent Fos expression in enkephalin and neurotensin neurons of the amygdala.

The neurotransmitters expressed by neurons activated by D-fenfluramine (5 mg/kg, i.p.) were identified in the hypothalamus, amygdala and bed nucleus of the stria terminalis. Induction of Fos immunoreactivity following D-fenfluramine injection was used as an index of neuronal activation. To test whether D-fenfluramine activated neurons by releasing serotonin from the serotonergic nerve terminals, rats were pretreated with fluoxetine (10 mg/kg, i.p.), a serotonin reuptake inhibitor that prevents the release of serotonin stimulated by D-fenfluramine, 12 h before D-fenfluramine injection. The approximate percentages of peptidergic neurons that contained Fos immunoreactivity after D-fenfluramine administration were 94% of corticotropin-releasing factor and 22% of oxytocin cells in the paraventricular nucleus of the hypothalamus, 6% of oxytocin cells in the supraoptic nucleus of the hypothalamus, 36% of enkephalin and 15% of neurotensin cells in the central amygdaloid nucleus, and 19% of enkephalin and 9% of neurotensin cells in the bed nucleus of the stria terminalis. Fluoxetine pretreatment blocked Fos expression in corticotropin-releasing factor- and oxytocin-expressing cells in the hypothalamus, but not in enkephalin-and neurotensin-expressing cells located in the bed nucleus of the stria terminalis and central amygdaloid nucleus. D-Fenfluramine did not induce Fos immunoreactivity in vasopressin-, thyrotropin-releasing hormone-, somatostatin- and tyrosine hydroxylase-containing cells in the hypothalamus, and corticotropin-releasing factor-expressing cells in the central amygdaloid nucleus and bed nucleus of the stria terminalis. These results show that D-fenfluramine stimulates corticotropin-releasing factor- and oxytocin-expressing cells in the hypothalamus via serotonin release. The enkephalin- and neurotensin-expressing cells in the amygdala are activated by D-fenfluramine via non-serotonergic mechanisms. Induction of Fos expression by D-fenfluramine in restricted populations of cells suggests a selective activation of neuronal circuitry that is likely to be involved in the appetite suppressant effects of D-fenfluramine.

Amygdala↗
PubMed2003

Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus.

Corticosterone regulates both basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity in a negative-feedback fashion. However, the cellular and molecular mechanisms of this negative feedback have yet to be explicitly characterized. By comparing stress-induced c-fos and corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus (PVN), we may be able to determine whether acute glucocorticoid treatment affects the net neural excitatory input to the PVN (represented primarily by c-fos mRNA expression) or directly affects the ability of cells in the PVN to respond to that input (represented primarily by CRH hnRNA expression). In the following studies, we observed the effect of acute glucocorticoid (RU28362) treatment on subsequent HPA axis reactivity by measuring stress-induced plasma hormone concentration [corticosterone and adrenocorticotropic hormone (ACTH)] and gene expression (c-fos and CRH) in the PVN. First, we examined the dose-response relationship between systemically administered RU28362 (1-150 microg/kg, i.p) and suppression of the stress-induced corticosterone response. We then confirmed central nervous system access of the maximally suppressive dose of RU28362 (150 microg/kg) by an ex vivo radioligand binding assay. RU28362 selectively occupied the majority of glucocorticoid receptors in the hippocampus and hypothalamus while having no effect on mineralocorticoid receptors. In separate studies, RU28362 (150 microg/kg) and corticosterone (5 mg/kg) were injected i.p. 1 h before restraint stress. Compared to vehicle-treated controls, rats treated with RU28362 and corticosterone had substantially blunted stress-induced corticosterone and ACTH production, respectively. Furthermore, treatment with RU28362 significantly blunted stress-induced CRH hnRNA expression in the PVN. By contrast, neither RU28362 nor corticosterone treatment had an effect on stress-induced neuronal activation as measured by c-fos mRNA and its protein product in the PVN. This dissociation between c-fos and CRH gene expression suggests that glucocorticoid suppression of HPA activity within this time-frame is not a result of decreased excitatory neural input to the PVN, but instead depends on some direct effect of RU28362 on cells intrinsic to the HPA axis.

Adrenocorticotropic Hormone↗
PubMed1990

Expression and purification of the leucine zipper and DNA-binding domains of Fos and Jun: both Fos and Jun contact DNA directly.

The protein products of the fos and jun protooncogenes interact cooperatively in the form of a heterodimer with the activator protein 1 (AP-1) regulatory element. To characterize the properties of these proteins, we have expressed polypeptides comprised of the dimerization and DNA-binding domains of Fos and Jun in Escherichia coli. The mini-Fos (wbFos) and the mini-Jun (wbJun) proteins were purified to apparent homogeneity by using a nickel affinity chromatography procedure. Purified wbFos and wbJun associated rapidly in vitro and interacted cooperatively with the human metallothionein IIA AP-1-binding site. However, efficient DNA binding of wbJun and wbFos-wbJun complexes required an additional activity present in nuclear extracts. This activity was sensitive to alkylating agents and could be partially mimicked by the presence of reducing and stabilizing agents. DNase I footprinting experiments demonstrated that Jun homodimeric complexes and Fos-Jun heterodimeric complexes interacted with the same site on the human metallothionein IIA gene. Moreover, UV-crosslinking studies demonstrated that Fos and Jun contact DNA directly and that both proteins interacted equivalently with either strand of the AP-1-binding site.

Amino Acid Sequence↗
PubMed1991

Cell-type specific multiprotein complex formation over the c-fos serum response element in vivo: ternary complex formation is not required for the induction of c-fos.

At the serum response element (SRE) of the c-fos proto-oncogene a ternary complex with two proteins, ternary complex factor (p62TCF) and serum response factor (SRF) can be formed. Its formation has previously been suggested to be necessary for efficient induction of c-fos transcription by serum in mouse NIH 3T3 fibroblasts (1) and by phorbol esters, but not by serum, in mouse BALB/c 3T3 fibroblasts (2). It is shown here by genomic dimethyl sulfate (DMS) footprinting that this ternary complex is indeed formed in NIH 3T3 cells in vivo. However, cells were found, murine F9 teratocarcinoma stem cells, in which the pattern of protection and hyperreactivity is consistent with the absence of p62TCF in the protein complex in vivo, although inducibility of the endogenous c-fos gene is not impaired. Both in NIH 3T3 cells and in F9 cells a mutated c-fos promoter that binds SRF but fails to form a ternary complex, was inducible by serum and phorbol esters to the same extent as the wild-type promoter. The data suggest that ternary complex formation is not an absolute prerequisite for the transient induction of c-fos. Ternary complex formation rather appears to enhance overall promoter efficiency. A cell type specific component determines the formation of the multicomponent transcription factor complex in vivo.

Animals↗
PubMed2000

Cloning, structural organization, and chromosomal assignment of the porcine c-fos proto-oncogene, FOS.

The complete porcine c-fos proto-oncogene (FOS) with flanking regions was cloned and sequenced. FOS consists of four exons at amino acids 1-47, 48-131, 132-167, and 168-380 and includes all the typical motifs of the fos proto-oncogene. The promoter contains consensus sequences for CRE, SRE, CaRE, and the E-Box, as well as an AP-1 site. Homologies between human and swine were between 89.7% and 96.3% in the exons. Based on somatic cell hybrid panel screening and known homologies between swine chromosome 7 and human chromosome 14, the porcine c-fos gene was assigned to chromosome 7q23.

Animals↗
PubMed1999

The tissue-specific transcription factor Pit-1/GHF-1 binds to the c-fos serum response element and activates c-fos transcription.

Pit-1, a POU domain-containing transcription factor, is involved in two functions in the pituitary: PRL and GH tissue-specific expression and somatolactotroph cells expansion. To analyze the molecular basis of the latter function, we tested whether Pit-1 can directly transactivate expression of an early marker of cell cycle initiation, the c-fos gene. We show that Pit-1 overexpression in PC12 cells, which do not express Pit-1, increases c-fos expression. Moreover, cAMP-induced c-fos promoter activity is decreased in the somatolactotroph cell line GH3 when Pit-1 expression is reduced by hybrid arrest with an antisense sequence complementary to Pit-1 cDNA. In contrast to hormonal genes regulation, where it has been shown that any Pit-1 phosphorylation site is involved, we show that the Pit-1 phosphorylation sites are required to allow increase of c-fos promoter activity by Pit-1. We further show, by gel shift analyses, that Pit-1 is able to specifically bind the serum response element sequence present within the c-fos promoter but with a lesser affinity than the Pit-1 response element. Taken together, these results demonstrate that the tissue-specific transcription factor Pit-1 is able to enhance expression of genes involved in cell cycle initiation, suggesting that this mechanism allows Pit-1 to increase somato-lactotroph cell proliferation.

Animals↗
PubMed2005

Neocortical c-fos mRNA transcription in repeated, brief, acute seizures: is c-fos a coincidence detector?

The effect of acute brief seizures on neocortical c-fos expression was investigated in rats injected with 5 mg/kg 4-aminopyridine. Electroencephalography in freely moving animals with implanted neocortical electrodes detected an average of 2.67 tonic-clonic convulsions within 1 h following the 4-AP treatment. Tissue samples of the somatosensory neocortex were collected at 30 min, 1 h, 3 h, 5 h and 8 h following the treatment for PCR and immunohistochemistry. The c-fos mRNA displayed the first significant rise at 1 h, and remained significantly higher through 3 h. The number of c-fos protein immunoreactive cells was significantly elevated already at 30 min, peaked at 1 h, and declined by 5 h. We conclude that in repetitive, brief seizures, the first convulsion does not increase c-fos RNA transcription, whilst the second causes a long-lasting gene expression and a large increase of c-fos protein synthesis. The phenomenon may have implications in the pathogenesis of human and animal epilepsies.

4-Aminopyridine↗
PubMed1984

Expression of the c-fos gene and of an fos-related gene is stimulated by platelet-derived growth factor.

Complementary DNA clones of genes induced by platelet-derived growth factor (PDGF) in BALB/c-3T3 cells were isolated; one such clone contains a domain having nucleotide sequence homology with the third exon of c-fos. This nucleotide sequence homology is reflected in the predicted amino acid sequences of the gene products. Under low stringency conditions, the mouse v-fos gene cross-hybridizes with the PDGF-inducible complementary DNA clone. However, the messenger RNA transcripts of mouse c-fos and the new fos-related gene can be distinguished by gel electrophoresis and by S1 nuclease analysis. Expression of the authentic c-fos gene is induced by PDGF and superinduced by the combination of PDGF and cycloheximide.

Amino Acid Sequence↗
PubMed2000

Activation of the c-fos enhancer by the erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites.

The c-fos enhancer can be activated by many signaling pathways through distinct elements of the enhancer. The enhancer contains at its core the serum response element (SRE) that binds serum response factor (SRF). On the 5' side of the SRE is a site for p62TCF which binds only when SRF is bound as well. p62TCF is encoded by three ets-related genes, Elk-1, SAP1 and SAP2. Each of these factors contain a transcriptional activation domain that is activated by phosphorylation by MAP kinases. On the 3' side of the SRE is the 'c-fos AP1 site' (FAP1) whose role has been less clear. We find here that the FAP1 site contributes strongly to phorbol ester (TPA) and Erk MAP kinase activation of the c-fos enhancer and that both the p62TCF and FAP1 sites are required for effective activation of the enhancer. We further find that the FAP1 site binds ATF1 and CREB from HeLa nuclear extracts and that the phosphorylation of these factors is induced by TPA. ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.

Activating Transcription Factor 1↗
PubMed1994

Visceral noxious stimulation induced expression of Fos protein in medullary catecholaminergic neurons projecting to nucleus accumbens in the rat: a study with triple labeling method of HRP tracing combined with Fos and TH immunohistochemistry.

Horseradish peroxidase (HRP) was stereotaxically injected into the nucleus accumbens (Acb), and visceral noxious stimulation given by injecting formalin into the stomach. Sections of the medulla were subjected to HRP reaction combined with immunohistochemical reactions for Fos protein (ABC method) and tyrosine hydroxylase (TH, PAP method). The catecholaminergic neurons of the medulla (including vagal complex, ventrolateral medulla and reticular formation between them) which expressed Fos protein and projected to Acb were studied. The results showed that HRP retrogradely labeled cells were seen in the medulla bilaterally with apparent ipsilateral predominance and TH-LI and Fos-LI single labeled cells were bilaterally distributed; HRP/TH,TH/Fos double labeled neurons were more numerous than HRP/Fos double-labeled neurons. HRP/TH/Fos triple-labeled neurons were small in number and were mainly distributed in the nucleus tractus solitarii (nTS) and ventrolateral medulla (VLM), but only a few labeled cells were located in RF between nTS and VLM. It is concluded that TH-LI neurons in the medulla projected to Acb and some of them expressed Fos protein after noxious stimulation of the stomach.

Animals↗
PubMed1998

Expression of c-fos, fos B, and egr-1 in the medial preoptic area and bed nucleus of the stria terminalis during maternal behavior in rats.

The spatial and temporal pattern of expression of the protein products of immediate early genes (IEGs) c-fos, fos B, and egr-1 were mapped in medial preoptic area (MPOA) and ventral bed nucleus of stria terminalis (VBST) during maternal behavior in rats. Immunocytochemical analysis indicated significant increases in the number of cells expressing c-Fos after 2 h of pup exposure, while Fos B levels showed a delayed response, reaching maximal levels after 6 h.

Animals↗