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PubMed1992

Colonic aberrant crypt foci are associated with increased expression of c-fos: the possible role of modified c-fos expression in preneoplastic lesions in colon cancer.

Aberrant crypt foci represent the earliest detectable lesions of colon cancer. The expression of c-fos in these aberrant crypts was determined by in situ hybridization and immunohistochemistry. These lesions were induced in the colonic epithelium with azoxymethane using the rat model system. Expression of c-fos was markedly increased in the aberrant colonic crypts. Increases of approximately 60 and approximately 70% in the proportion of epithelial cells labelled were observed in the early and advanced aberrant crypts respectively. This was found to be statistically significant (P less than 0.001). Consistent with cell proliferation patterns in the colonic crypts, the epithelial cells of the lower crypt had greater levels of c-fos mRNA than those of the upper part of the crypts. In addition, immunohistochemical staining with c-fos polyclonal antibodies demonstrated increased levels of c-fos protein in aberrant crypts. This combined approach using in situ hybridization and immunohistochemistry has shown that increased c-fos expression at the RNA level in these lesions is associated with increased amounts of c-fos protein. Since c-fos has been implicated in the process of cell proliferation and differentiation, modifications in its expression may be significant to understanding the mechanisms whereby preneoplastic lesions transform to neoplastic lesions in colon cancer.

Animals↗
PubMed1990

The NMDA receptor mediates cortical induction of fos and fos-related antigens following cortical injury.

Cortical cavity lesions and lateral ventricular injections of quinolinic acid, a NMDA receptor agonist, induce Fos and Fos-related antigens (FRAs) throughout ipsilateral adult rat brain cortex in similar patterns. c-fos mRNA, assessed using in situ hybridization, was induced by 1 h and disappeared between 3 and 8 h following cortical lesions. Fos proteins, detected using a specific monoclonal antibody, were induced by 1 h and disappeared by 4 h after cortical lesions. FRA proteins, detected using polyclonal antibodies, were induced between 1 and 4 h and persisted for at least 72 h following focal cortical injury. Intraventricular injections of CPP, a competitive NMDA receptor antagonist, completely blocked the induction of these nuclear proteins in cortex ipsilateral to the focal cortical lesions--except around the injury site itself. Intraventricular injections of quisqualate, a non-NMDA glutamate analogue, induced Fos in hippocampus but not in cortex. These data show that NMDA receptors mediate the induction of Fos and FRAs following cortical injury. It is proposed that local cortical injury releases excitatory amino acids that act at NMDA receptors to initiate spreading depression and that the resultant depolarization induces Fos in neurons throughout the cortex. Since Fos and FRAs are proteins that regulate the expression of target genes, they could mediate long-term biochemical adaptations in neurons following cortical injury.

Animals↗
PubMed2002

Ultraviolet B (UVB) induction of the c-fos promoter is mediated by phospho-cAMP response element binding protein (CREB) binding to CRE and c-fos activator protein 1 site (FAP1) cis elements.

The ultraviolet B (UVB) portion (280-320 nm) of the ultraviolet spectrum has been shown to contribute to the development of non-melanoma skin cancer in humans. Research in the human keratinocyte cell line, HaCaT, revealed that UVB irradiation caused the upregulation of the transcription factor activator protein-1 (AP-1). The AP-1 complex formed in UVB-irradiated HaCaT cells is specifically composed of c-fos and Jun D. c-Fos expression was induced in a manner that correlated with the UVB-induced activation of AP-1. To investigate how c-fos expression is regulated by UVB irradiation, the role of each of four cis elements within the c-fos promoter was evaluated. Clustered point mutations at the sis inducible element (SIE), serum response element (SRE), c-fos AP-1 site (FAP1), or cyclic AMP response elements (CRE) significantly inhibited UVB induction of the c-fos promoter. This indicated that all four cis elements are required for maximum promoter activity. The CRE and FAP1 elements were the two most active cis elements that mediate the UVB transactivation of c-fos. Homodimers of phosphorylated cAMP response element binding protein (CREB) were induced by UVB irradiation to bind to each of these elements. Therefore, CREB may function as an important regulatory protein in the UVB-induced expression of c-fos.

Binding Sites↗
PubMed2000

The temporal course of expression of c-Fos and Fos B within the medial preoptic area and other brain regions of postpartum female rats during prolonged mother--young interactions.

Maternal behavior is associated with an increase in the expression of c-Fos and Fos B within neurons of the medial preoptic area (MPOA) and ventral bed nucleus of the stria terminalis (vBST). Whether this increase wanes as the duration of mother-young interaction increases is unknown. By varying the length of mother-young interactions in postpartum rats, the authors found that within the MPOA/vBST, the levels of both c-Fos and Fos B, once elevated, remained significantly above control levels through 47 hr of pup exposure. The persistence of c-Fos and Fos B within the MPOA/vBST of females that remained with pups was almost unique in that only one other neural area, the anterior magnocellular part of the paraventricular hypothalamic nucleus, showed such a response. Because MPOA/vBST neurons are essential for maternal behavior, the results suggest that c-Fos and Fos B expression within these regions may be necessary to maintain their normal functional activity.

Animals↗
PubMed2001

Control of the orientation of Fos-Jun binding and the transcriptional cooperativity of Fos-Jun-NFAT1 complexes.

Heterodimeric transcription regulatory proteins can bind to palindromic recognition elements in two opposite orientations. We have developed a gel-based fluorescence resonance energy transfer assay for quantifying heterodimer orientation preferences. Fos-Jun heterodimers bind in opposite orientations to AP-1 sites with different flanking sequences. The effects of individual amino acid and base pair substitutions on heterodimer binding orientation were quantified. Base pairs at positions +/-6 and +/-10 relative to the center of the AP-1 site were the principal determinants of Fos-Jun binding orientation. Amino acid residues of opposite charge adjacent to the basic regions of Fos and Jun had independent effects on heterodimer orientation. Exchange of these amino acid residues between the basic region-leucine zipper domains of Fos and Jun reversed the binding orientation. Heterodimers formed by full-length Fos and Jun exhibited the same changes in binding orientation in response to amino acid and base pair substitutions. The preferred orientation of heterodimer binding affected the stability of Fos-Jun-NFAT1 complexes at composite regulatory elements. Changes in heterodimer orientation preference altered the transcriptional activity and the promoter selectivity of Fos-Jun-NFAT1 complexes. Consequently, the orientation of Fos-Jun binding can influence transcriptional activity by altering cooperative interactions with other transcription regulatory proteins.

Amino Acid Sequence↗
PubMed1989

Expression of the proto-oncogene fos (c-fos) by preimplantation blastocysts of the pig.

Blastocyst material was obtained from 25 pigs during the period 10 to 33 days post coitum, and fixed thin sections of tissue were hybridized in situ to sense and antisense fos RNA probes synthesized using the expression vector Bluescribe M13. Indirect immunofluorescence using antisera to a synthetic peptide fragment of c-fos was used to confirm the tissue distribution of oncogene-encoded proteins, which were shown by immunoprecipitation to have Mrs of 55,000 and 40,000, which are the known Mrs of the fos gene product and an associated nucleoprotein, respectively. Northern and slot blots were used to assess the distribution of c-fos mRNA and the size of the fos transcript was found to be 2.3 kbases. C-fos was expressed in trophectoderm from blastocysts early in pregnancy but declined with increasing blastocyst development so that it was virtually absent by day 19 of gestation. High levels of fos proto-oncogene expression were, however, retained in the allantoic membranes up to at least day 19 of pregnancy. The expression of the fos protein could be prolonged in trophectodermal cells in monolayer culture by addition of conditioned medium from blastocysts cultured for 2 h, suggesting the presence of a growth-factor-like substance.

Amino Acid Sequence↗
PubMed1987

Proto-oncogene fos (c-fos) expression in the heart.

Administration of the beta-adrenergic agonist isoproterenol led to a marked rapid increase in the steady-state level of c-fos mRNA in the heart of mice, rats, and Syrian hamsters. Stimulation of c-fos expression by isoproterenol was inhibited by the beta-adrenergic antagonist propranolol. An increase in Ca2+ influx through voltage-dependent calcium channels is probably not required for the activation of the c-fos gene by isoproterenol since the calcium channel blockers verapamil, nifedipine, and diltiazem had no effect on the induction of c-fos by the drug. In the heart of the rat, c-fos expression was also stimulated by the alpha-adrenergic agonist phenylephrine, histamine, and prostaglandin E1. The histamine-induced expression of the c-fos gene was blocked by the histamine H1-receptor antagonist pyrilamine but not by H2-receptor antagonists ranitidine and cimetidine. It is concluded that in the heart, hormones which increase cAMP and cytosolic Ca2+, such as beta-adrenergic agonists and prostaglandin E1, and/or stimulate the turnover of inositol phospholipids, such as alpha-adrenergic agonists and histamine H1-receptor agonists, regulate c-fos gene expression. The fos protein is likely to play a role in the mechanisms of neurotransmitters and hormones that modulate the functioning of the heart and of cardiac hypertrophy, degeneration and necrosis.

Alprostadil↗
PubMed2000

Sleep and wakefulness in c-fos and fos B gene knockout mice.

G-protein coupled receptor (GPCR) stimulation has been implicated in the regulation of sleep. Upon stimulation of a GPCR an intracellular cascade involving second and third messengers is initiated. The latter include the fos-family of immediate early genes (IEGs). Although there is considerable evidence indicating that IEGs are expressed in response to sleep, the effects of their deletion on sleep is not known. The present study examined sleep-wakefulness in mice lacking the c-fos or fos B genes. Null c-fos mice compared to their wildtype (WT) and heterozygote (het) siblings had more wakefulness and less slow wave sleep (SWS); REM sleep was not affected. The null c-fos mice also had increased delta activity (0.3-4 Hz). In contrast, the null and heterozygote fos B mice had less REM sleep, but the time spent in SWS or wakefulness was not different from their wild-type (WT) siblings. In the null c-fos mice, the increased wakefulness and the reduction in SWS could not be due to a systemic alteration in temperature since the core temperature was similar in all mice. By demonstrating that these IEGs are involved in sleep, we suggest that the deletion of specific genes, even within a family of genes, can have a specific effect on sleep.

Animals↗
PubMed1992

Targeted degradation of c-Fos, but not v-Fos, by a phosphorylation-dependent signal on c-Jun.

The proto-oncogene products c-Fos and c-Jun heterodimerize through their leucine zippers to form the AP-1 transcription factor. The transcriptional activity of the heterodimer is regulated by signal-dependent phosphorylation and dephosphorylation events. The stability of c-Fos was found to also be controlled by intracellular signal transduction. In transient expression and in vitro degradation experiments, the stability of c-Fos was decreased when the protein was dimerized with phosphorylated c-Jun. c-Jun protein isolated from phorbol ester-induced cells did not target c-Fos for degradation, which suggests that c-Fos is transiently stabilized after stimulation of cell growth. v-Fos protein, the retroviral counterpart of c-Fos, was not susceptible to degradation targeted by c-Jun.

Amino Acid Sequence↗
PubMed1992

Inhibition of Fos- and Ras-induced transformation by mutant Fos proteins with structural alterations in functionally different domains.

We show that transformation-defective Fos proteins lacking either a functional leucine zipper (mutants L345 and J/R510s) or the 110 amino-terminal amino acids (mutant BR800) inhibit the induction of morphological transformation by v-Fos. Both types of mutants specifically repress transformation without any significant effect on cell proliferation. In contrast, several transformation-defective Fos mutants with structural alterations in the acidic region or the right half of the adjacent basic DNA contact site do not show any inhibition of transformation. This result, taken together with the repression of transformation by the leucine zipper-deficient mutants L345 and J/R510s, indicates that the interaction of Fos with proteins other than Jun is necessary for transformation. The leucine zipper-deficient mutants also inhibit Fos-mediated activation of AP-1-dependent transcription. This suggests that their inhibitory effect on transformation may at least in part be the result of the squelching of proteins other than Jun family members that are required for Fos-mediated transactivation. All three mutants were also found to inhibit transformation by the point-mutated H-ras oncogene from EJ carcinoma cells and to trigger a partial reversion of the transformed phenotype of Ras-transformed fibroblasts. These findings support the conclusion that Ras-induced transformation involves signal transduction pathways inducing the c-fos gene.

Cell Division↗
PubMed1997

Inhibition of carrageenan-induced spinal c-Fos activation by systemically administered c-fos antisense oligodeoxynucleotides may be facilitated by local opening of the blood-spinal cord barrier.

Proto-oncogenes of the fos and jun family are rapidly expressed in the central nervous system following various stimuli. Proto-oncogene encoded nuclear proteins such as c-Fos or c-Jun act as transcription factors that may link neuronal excitation to changes in target gene expression. However, the precise in vivo functions of proto-oncogenes in neuroplasticity are still poorly understood. In the present study the effect of systemically administered c-fos antisense oligodeoxynucleotides (ODNs) on c-Fos and dynorphin protein levels in rat L4 spinal cord has been investigated by immunohistochemistry during carrageenan-induced hindpaw inflammation. Continuous infusion of terminal-phosphorothioated c-fos antisense ODNs by subcutaneously implanted miniosmotic pumps for 3 days sequence-specifically suppressed c-Fos protein expression in dorsal horn neurons by about 50%, while the increase in c-Jun immunopositive nuclei was not affected. Digital image analysis revealed a concomitant decrease in spinal dynorphin immunoreactivity. Moreover, 48 hr after carrageenan injection into one hindpaw plasma protein extravasation was observed in numerous blood vessels in the ipsilateral dorsal horn using intravenously administered Evans Blue. Our results provide further evidence that c-Fos may contribute to the regulation of spinal dynorphin gene expression following noxious stimulation. The local increase in blood-spinal cord barrier permeability during sustained peripheral inflammation may permit penetration of hydrophilic antisense ODNs into the central nervous system.

Animals↗
PubMed1990

Mutual transrepression of Fos and the glucocorticoid receptor: involvement of a functional domain in Fos which is absent in FosB.

In this study, we show that Fos protein can repress transactivation by the glucocorticoid receptor (GR). In addition, we demonstrate that GR is capable of inhibiting, in a hormone-dependent fashion, Fos-mediated transactivation of AP-1 dependent transcription. Moreover, repression of the serum response element by Fos is abolished by the GR in the presence of hormone. Transrepression of glucocorticoid mediated induction involves a region of Fos, located between amino acids 40 and 111, to which no function has been previously assigned, and which is poorly conserved among Fos, FosB and Fra-1. In agreement with this finding, FosB is not capable of transrepressing GR activation of transcription, representing the first functional difference between Fos and FosB. We have mapped the domain of the GR which is required for repression of AP-1 dependent transcription, to the region of central DNA binding domain. Our results suggest that Fos and the GR may form transcriptionally inactive complexes and point to a regulatory interrelationship between different signal transduction pathways.

Amino Acid Sequence↗
PubMed1992

Basal expression of Fos, Fos-related, Jun, and Krox 24 proteins in rat hippocampus.

The basal expression of the protein products of the inducible immediate early genes (IEGs), Fos, Jun, and Krox 24, was investigated in rat hippocampus using immunocytochemical visualization methods with antisera specific for Fos only, Fos and the Fos-related antigens (FRAs), the Jun family, and Krox 24 (previously described as TIS 8, egr-1, NGF-IA or zif 268). In the normal adult rat brain basal levels of Jun, Krox 24 and Fos-related antigens but not Fos were seen within the hippocampus. More specifically very high basal levels of Jun were seen in the dentate granule cells with high basal Krox 24 levels seen in the CA1-subiculum region of the rat hippocampus. Basal FRAs but not Fos-positive cells were seen at low levels in the dentate granule cells. The implications of these results to the functioning of IEG proteins in hippocampal neurons is discussed.

Animals↗
PubMed1994

Differential induction of Fos protein and a Fos-related antigen following acute and repeated cocaine administration.

The present study examined the effects of a single and five once daily injections of cocaine on the expression of c-fos mRNA, Fos protein and Fos-related antigens (Fra) in the striatum. A single injection (40 mg/kg, i.p.), which induces locomotion, increased the expression of c-fos mRNA, Fos protein and a 35 kDa Fra. In contrast, five injections (40 mg/kg, i.p.) given once a day, which induces even more behavioral stimulation, diminished the increase in c-fos mRNA and Fos protein expression. However, the cocaine-induced Fra expression was sustained and not reduced after the five injections. The results demonstrate that cocaine-induced expression of the Fos/Fra gene family is dynamic and the profile of gene transcription and translation in the striatum changes when animals are behaviorally more sensitive to cocaine.

Animals↗
PubMed1996

Expression of c-fos and fos-B proteins following transient forebrain ischemia: effect of hypothermia.

Immediate early genes are induced by transient global ischemia. Using immunohistochemistry we studied the effect of intraischemic hypothermia (30 degrees C) on the expression of c-fos and fos-B proteins following 10 min forebrain ischemia in the gerbil. Postischemia (PI) periods of 1 hour (h), 6 h, 1 day (d) and 2 d and nonischemic controls were examined in normothermic and hypothermic brains. In normothermic ischemic brains, marked expression of c-fos occurred in the dentate gyrus after 1 h PI which extended to CA2-4 regions by 6 h. Hypothermia hastened the time course of c-fos expression as it was expressed simultaneously in the dentate gyrus as well as CA2-4 regions after only 1 h, and by 6 h the expression remained only in the CA2-4 regions and not the dentate gyrus in hypothermic ischemic brains. There was no difference in its expression between normothermic and hypothermic brains in the 1 d and 2 d PI animals. Somewhat similar changes were noted in fos-B expression. In normothermic ischemic brains fos-B was induced in the dentate gyrus by 1 h PI, and by 6 h it extended to involve CA1-4 cells. The hypothermic ischemic brains showed faster induction of fos-B so that the dentate gyrus as well as CA1-4 regions were immunopositive at 1 h PI. There was no difference in its expression between normothermic and hypothermic brains in the subsequent PI periods of 6 h, 1 d and 2 d. The shift towards faster sequential induction of these genes by hypothermia in ischemic brains may be indicative of preservation of or faster recovery of mechanisms involved in intracellular signalling.

Animals↗
PubMed2000

Co-stimulation of D(1)/D(5) and D(2) dopamine receptors leads to an increase in c-fos messenger RNA in cholinergic interneurons and a redistribution of c-fos messenger RNA in striatal projection neurons.

The anatomical subdivision of striatum in patch and matrix compartments plays an important role for the processing of neurotransmission through the basal ganglia in primates and rodents. Here we report that co-administration of D(1)/D(5) and D(2) receptor agonists, which induces a heterogenous and patchy pattern of c-fos messenger RNA expression in striatum, stimulates c-fos messenger RNA expression in cholinergic interneurons. Moreover, this treatment induces c-fos messenger RNA in projection neurons containing D(1)-, rather than D(2)-receptor messenger RNA. The preferential induction of c-fos messenger RNA in patches does not depend upon a higher degree of co-localization between D(1) and D(2) receptors in this area, since double in situ hybridization experiments showed a large segregation of D(1) and D(2) receptor messenger RNAs in the patch as well as the matrix compartments. By contrast, treatment with a full D(1)/D(5) receptor agonist up-regulates striatal c-fos messenger RNA homogenously and in similar proportions of D(1) and D(2) receptor messenger RNA-containing projection neurons in both medial and lateral striatum, but has only minor effects on c-fos messenger RNA expression in cholinergic interneurons. These results provide a neuroanatomical/neurochemical correlate to the well-known behavioral interaction between dopamine D(1)/D(5) agonists and dopamine D(2) agonists. They also suggest that there may be a relation between a heterogenous, patch-enriched c-fos messenger RNA expression and an increased expression of this immediate early gene in cholinergic interneurons.

Animals↗
PubMed1994

c-fos antisense attenuates Fos expression in rat central neurons induced by hemorrhage.

Hemorrhage caused by withdrawing 3-4 cm3 of blood from adult rats over a period of 1-2 h induced the expression of Fos proteins, which were detected by immunocytochemical methods in neurons of the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei, area postrema, nucleus of the solitary tract (NTS), ventrolateral medulla (VLM) and in intermediolateral cell column (IML) of the spinal cord. Daily intraventricular (i.c.v.) injections of c-fos antisense (50 nmol 5 microliters -1) for 2 days prior to hemorrhage markedly attenuated the extent and intensity of Fos-immunoreactivity (FOS-IR) compared with that of rats injected with c-fos sense in the areas mentioned above. The results indicate the effectiveness of i.c.v. administration of c-fos antisense in blocking Fos expression in central neurons following hemorrhage.

Animals↗
PubMedDate not supplied

C-fos antisense oligodeoxynucleotide decreases subcutaneous bee venom injection-induced nociceptive behavior and fos expression in the rat.

Oligodeoxynucleotide complementary to c-fos mRNA was applied to characterize its effect on the spinal cord Fos expression and relevant nociceptive behaviors challenged by subcutaneous injection of bee venom to the rat hind paw. Nociceptive behavioral responses (spontaneous pain and hyperalgesia) following bee venom (0.2 mg/50 microl) injection were assessed in adult male Sprague-Dawley rats receiving intrathecal administration of c-fos antisense oligodeoxynucleotide (ASO, 50 microg/10 microl), sense oligodeoxynucleotide (SO, 50 microg/10 microl) and saline (10 microl) 4 h prior to bee venom injection. The lumbar spinal cord expression of Fos protein 2 h after bee venom injection in the ASO-, SO- and saline-treated animals was observed by immunohistochemistry. The results showed that pretreatment of c-fos ASO markedly reduced the flinching response and primary thermal hyperalgesia, but without significant effects on mechanical hyperalgesia and secondary thermal hyperalgesia. At the same time, ASO treatment also significantly decreased the expression of Fos protein within the lumbar region of the spinal cord ipsilateral to the injection. The results provide further evidence that Fos protein contributes to the activation of the spinal dorsal horn neurons and the generation and/or maintenance of spontaneous pain and primary thermal hyperalgesia induced by subcutaneous injection of bee venom.

Afferent Pathways↗