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PubMed2000

Regulation of FOS by different compartmental stresses induced by low levels of ionizing radiation.

We irradiated different cellular compartments and measured changes in expression of the FOS gene at the mRNA and protein levels. [(3)H]Thymidine and tritiated water were used to irradiate the nucleus and the whole cell, respectively. (125)I-Concanavalin A binding was used to irradiate the cell membrane differentially. Changes in FOS mRNA and protein levels were measured using semi-quantitative RT-PCR and SDS-PAGE Western blotting, respectively. Irradiation of the nucleus or the whole cell at a dose rate of 0.075 Gy/h caused no change in the level of FOS mRNA expression, but modestly (1.5-fold) induced FOS protein after 0.5 h. Irradiation of the nucleus at a dose rate of 0.43 Gy/h induced FOS mRNA by 1.5-fold after 0.5 h, but there was no significant effect after whole-cell irradiation. FOS protein was transiently induced 2.5-fold above control levels 0.5 h after a 0. 43-Gy/h exposure of the nucleus or the whole cell. Irradiation of the cell membrane at a dose rate of 1.8 Gy/h for up to 2 h caused no change in the levels of expression of FOS mRNA or protein, but a dose rate of 6.8 Gy/h transiently increased the level of FOS mRNA 3-fold after 0.5 h. These data demonstrate the complexity of the cellular response to radiation-induced damage at low doses. The lack of quantitative agreement between the transcript and protein levels for FOS suggests a role for post-transcriptional regulation.

Cell Membrane↗
PubMed1990

Activation of mouse osteoblast growth hormone receptor: c-fos oncogene expression independent of phosphoinositide breakdown and cyclic AMP.

Addition of human GH (hGH) to primary mouse osteoblasts resulted in rapid and transient induction of the c-fos and c-myc proto-oncogenes and preceded hGH-induced mitogenesis. Human GH-induced c-fos expression was maximal after 30 min, resulting in a 10- to 15-fold increase over unstimulated cells, and returned to prestimulation levels within 60 min of the addition of hGH. Induction of the c-fos gene by hGH was dose dependent and also occurred in the absence of protein synthesis, resulting in superinduction of the c-fos gene. The induction of the c-fos gene by hGH was mediated by a somatotrophic (GH) rather than a lactogenic (prolactin) receptor on primary mouse osteoblasts, as indicated by a 10- to 100-fold greater potency of hGH compared with ovine prolactin in stimulating the expression of the c-fos gene. Primary mouse osteoblasts also induced the c-fos gene in response to epidermal growth factor, insulin-like growth factor-I and several agents, including phorbol 12-myristate 13-acetate (TPA), forskolin and A23187, that are known to activate signal transduction pathways involved in the action of growth factors. Addition of hGH to primary mouse osteoblasts did not result in increased phosphoinositide breakdown, while selective deactivation of the diacylglycerol-protein kinase C and inositol 1,4,5-trisphosphate-Ca2+ pathways by long-term TPA pretreatment or depleting intracellular Ca2+ stores had no effect on hGH-induced c-fos expression. Human GH did not alter basal cyclic AMP levels in mouse osteoblasts. The immediate consequences of GH-receptor interaction as well as the mechanism of signal transduction leading to induction of the c-fos gene remain, therefore, unresolved.

Animals↗
PubMed1999

Vomeronasal neuroepithelium and forebrain Fos responses to male pheromones in male and female mice.

Male urinary pheromones modulate behavioral and neuroendocrine function in mice after being detected by sensory neurons in the vomeronasal organ (VNO) neuroepithelium. We used nuclear Fos protein immunoreactivity (Fos-IR) as a marker of changes in neuronal activity to examine the processing of male pheromones throughout the VNO projection pathway to the hypothalamus. Sexually naive male and female Balb/c mice were gonadectomized and treated daily with estradiol benzoate (EB) or oil vehicle for 3 weeks. Subjects were then exposed to soiled bedding from gonadally intact Balb/c males or to clean bedding for 90 min prior to sacrifice and processing of their VNOs and forebrains for Fos-IR. Male pheromones induced similar numbers of Fos-IR cells in the VNO neuroepithelium of oil-treated male and female subjects; however, EB-treated females had significantly more Fos-IR neurons in the VNO than any other group. There was an equivalent neuronal Fos response to male odors in the mitral and granule cells of the anterior and posterior accessory olfactory bulb of males and females, regardless of hormone treatment. In central portions of the VNO projection pathway (i.e., bed nucleus of the stria terminalis, medial preoptic area) neuronal Fos responses to male pheromones were present in female but absent in male subjects, regardless of hormone treatment. In a separate experiment, mating induced neuronal Fos-IR in these brain regions at levels in gonadally intact male subjects which were equal to or greater than those seen in ovariectomized females primed with estrogen and progesterone. This suggests that neurons in the central portions of the male's VNO pathway are capable of expressing Fos. Our results suggest that sexually dimorphic central responses to pheromones exist in mice that may begin in the VNO neuroepithelium.

Animals↗
PubMed1999

c-Fos expression in the myenteric plexus, spinal cord and brainstem following injection of formalin in the rat colonic wall.

Fos expression induced by injection of dilute formalin (50 microl, 5% in physiological saline) into the colonic wall was examined in the myenteric plexus, lumbosacral spinal cord and brainstem of the rat. The aims of this study were (i) to determine whether neurons in these regions express Fos in response to the injection of formalin into the colon and (ii) to examine whether administration of an alpha 2 adrenoceptor agonist modulates Fos expression. Tissues were removed 2 h after the injection of saline or formalin. Saline injected in the colon induced Fos in enteric glia in the myenteric plexus. The number of Fos immunoreactive nuclei significantly increased in both myenteric neurons and enteric glia after the injection of formalin. Similarly, Fos immunoreactive neuronal nuclei were significantly increased in the spinal cord, area postrema and nucleus of the solitary tract after the injection of formalin. Pretreatment of rats with the alpha 2 adrenoceptor agonist xylazine (2, 4 and 8 mg/kg) 15 min before the injection of formalin, dose-dependently reduced the number of Fos immunoreactive neuronal and glial nuclei in the myenteric plexus, and neuronal nuclei in the spinal cord and brainstem. Simultaneous administration of xylazine (8 mg/kg) and the alpha 2 adrenoceptor antagonist yohimbine (1 mg/kg) reversed the effects of xylazine in the spinal cord and brainstem, but not in the myenteric plexus. These data show that injection of formalin in the colonic wall results in Fos expression in myenteric neurons and enteric glia, and neurons in the spinal cord and brainstem. This may be due to the direct chemical stimulation of the innervation of the colon and/or the subsequent acute colitis. The observed neuronal Fos expression can be modulated by an alpha 2 adrenoceptor agonist through noradrenergic pathways and/or reduction of the excitability of the enteric neural circuitry.

Adrenergic alpha-Agonists↗
PubMed2000

On the functional significance of c-fos induction during the sleep-waking cycle.

A striking finding in recent years has been that the transition from sleep to waking is accompanied in many brain regions by a widespread activation of c-fos and other immediate-early genes (IEGs). IEGs are induced by various electrical or chemical signals to which neural cells are exposed and their protein products act as transcription factors to regulate the expression of other genes. After a few hours of sleep, the expression of these transcription factors in the brain is absent or restricted to very few cells. However, after a few hours of spontaneous waking or sleep deprivation, the expression of c-fos and other IEGs is high in cerebral cortex, hypothalamus, septum, and several thalamic and brainstem nuclei. While cells expressing c-fos during waking are widely distributed, they represent only a subset of all neurons in any given area. These observations raise several questions: Why is c-fos expressed during waking and not during sleep? Is waking always accompanied by c-fos induction? Which subset of cells express c-fos during waking and why only a subset? Once c-fos has been induced, what are the functional consequences of its activation? In this review, we summarize our current understanding of the meaning of c-fos activation in the brain in relation to the sleep-waking cycle and suggest that c-fos induction in the cerebral cortex during waking might be related to the occurrence of plastic phenomena.

Animals↗
PubMed2001

[Effect of methylmercury chloride on the c-fos expression in brain nerve cells of the rats].

OBJECTIVE: In order to study the mechanism of injury in the brain development caused by methylmercury chloride (MMC) and its effects on the c-fos expression in brain nerve cells of the rats with experiments in vitro and in vivo. METHODS: In vitro, the effect of MMC on c-fos expression in the cultured nerve cells was observed by immunocytochemistry(SP method). In vivo, Wistar pregnant rats were administered 4 mg MMC per kg of body weight by a gastric tube from the 7th to the 10th gastational days. On the 1st, 3rd, 5th, 7th, 10th and 15th days after birth, the rats were killed and tissue sections were prepared from their brain, respectively. The expression of c-fos was detected by SP method. RESULTS: The percentage of c-Fos-positive neuron in rats brain began to increase at 0.5 hours after being cultured in in vitro with 0.3 mumol/L MMC continuously, and increased gradually as length of the exposure to MMC prolonged. The percentage of c-Fos-positive of cultured nerve cells in vitro were (6.97 +/- 2.86)%, (66.86 +/- 5.32)% and (64.49 +/- 3.09)% in the experimental groups exposed to MMC for 10 min, 2 h and 6 h, respectively. In vivo, the percentage of Fos-positive neuron nuclei decreased with development of neonatal rats. The percentage of c-Fos-positive neuron in the experimental groups was higher than that in the control groups and decreased with length of development. The percentages of c-Fos-positive neuron were (47.01 +/- 3.79)% and (46.71 +/- 1.96)% in the experimental group 1 and 3 d, and (35.8 +/- 3.04)% and (33.35 +/- 1.06)% in the control group, respectively, with very significant difference. CONCLUSIONS: It is concluded that MMC could induce c-fos over-expression in the nerve cells of the rat brain, which could explain the mechanism of injury to brain development caused by MMC.

Animals↗
PubMed2001

[Protective effect of c-fos antisense oligonucleotides on brain damage induced by glutamate].

OBJECTIVE: To investigate the relation between glutamate neurotoxicity and c-fos gene expression. METHODS: c-fos antisense oligonucleotides (AS ODN) was injected into the right lateral ventricles of 9 SD rats to block the c-fos gene expression in brain tissue. c-fos sense oligonucleotides (S ODN) was used a control. The numbers and morphology of neurons in both cerebral cortex and hippocampal CA1 were detected by MIAS-300 image analysing instrument. c-fos gene expression in brain was observed by immunohistochemical method. The content of water and electrolytes in the brain tissue and Ca(2+) in the synapse were measured. RESULTS: The c-fos AS ODN blocked the c-fos gene expression and reduced the content of both water and sodium in brain tissue and Ca(2+) in symptosome, thus alleviating the morphological damage in neuron. S ODN did not have such effect. CONCLUSION: c-fos gene expression plays an important role in mediating the effect of glutamate neurotoxicity. Blocking the c-fos gene expression could antagonize glutamate neurotoxicity.

Animals↗
PubMed1999

[Observations on expression of c-fos and c-myc genes and activity of PDGFBB autocrine loop in 67 human gliomas].

OBJECTIVE: To investigate the variance of expression of c-fos and c-myc genes and the activity of platelet-derived growth factor (PDGF) BB autocrine loop in human gliomas as well as their relationship. METHODS: In situ hybridization and immunohistochemistry were used to study 67 human glioma specimens of different grades. RESULTS: The incidences, of positive expression for c-fos mRNA, c-fos protein, c-myc mRNA and c-myc protein were 100% (67/67), 100% (67/67), 85.1% (57/67) and 83.6% (56/67) respectively. There was significant positive correlation between the positive cell densities of c-fos mRNA (92.49 +/- 33.87) and c-fos protein (91.64 +/- 38.11), and of c-myc mRNA (72.70 +/- 40.56) and c-myc protein (71.49 +/- 41.11, r = 0.917 - 0.988, P < 0.001). All of them also increased correspondingly with the malignant degree of the tumors and level of PDGFB mRNA expression in the tumor cells (P < 0.05 - 0.01). Not only were the positive cell densities of PDGF alpha receptor (58.46 +/- 28.77), PDGF beta receptor (63.03 +/- 31.63) and phosphotyrosine protein (68.25 +/- 29.30) correlated positively with one another (r = 0.827 - 0.896, P < 0.001), but they also all correlated positively with the positive cell densities of PDGFB mRNA, c-fos mRNA, c-fos protein, c-myc mRNA and c-myc protein respectively (r = 0.615 - 0.888, P < 0.001). CONCLUSIONS: The abnormally increased activity of the PDGFBB autocrine loop possibly upregulated the overexpression of c-fos and c-myc genes in glioma cells and suggested that c-fos and c-myc proteins probably played an important role as downstream response factors in the signaling pathway in which PDGFBB could induce gliocyte transformation and glioma development.

Adolescent↗
PubMed2000

[Increased expression of formalin-induced Fos and NADPH-d positive neurons in the spinal cord of morphine-tolerant rats].

Fos immunocytochemistry, NADPH-d histochemistry and Fos/NADPH-d double-labeling method were used to study the changes in formalin-induced Fos, NADPH-d positive and Fos/NADPH-d double-labeled neurons in the spinal cord of morphine-tolerant rats. Formalin-induced Fos-like immunoreactivity (Fos-LI) was located in the superficial laminae and neck of ipsilateral spinal cord. Acute administration of morphine decreased the expression of Fos-LI in non-tolerant rats, while the expression of Fos-LI was significantly increased in morphine-tolerant rats. Fos-LI was distributed not only in the whole laminae of the ipsilateral spinal cord but also in the contralateral spinal cord. Acute administration of morphine was ineffective in decreasing the expression of Fos-LI in morphine-tolerant rats. Morphine tolerance increased the expression of formalin-induced NADPH-d positive neurons in the superficial laminae of spinal dorsal horn. A few formalin-induced Fos/NADPH-d double-labeled neurons were detected in the superficial laminae of spinal dorsal horn of non-tolerant rats. In morphine-tolerant rats, on the other hand, formalin-induced Fos/NADPH-d double-labeled neurons were increased and distributed in the whole laminae of the ipsilateral spinal cord and the contralateral superficial spinal cord. It is suggested that NO is involved in the increase of formalin-induced Fos-LI in the spinal cord of morphine-tolerant rats and may play an important role in the development of morphine tolerance.

Animals↗
PubMed2004

Protein kinase C is partly involved in c-fos protein expression of nocuously-activated neurons but may not in concomitant modulatory action through opioid receptors at the spinal level in rats.

The present study was aimed to examine if protein kinase C (PKC) activation is necessarily involved in both the c-fos protein expression in the nocuously-activated c-fos protein-like immunoreactive (Fos-LI) neurons and the concomitant opioid receptor-mediated modulation in the dorsal horn circuitry of the spinal cord. Formalin was injected into a hindpaw of rats 5 min after the rats were pretreated with intrathecal (i.t.) administration of chelerythrine (Chel), an inhibitor of PKC, naloxone (Nal), combined administration of these two (Chel + Nal), or vehicle (n=5 in each group),respectively. By using immunocytochemical techniques, the formalin-induced Fos-LI neurons in the lumbar dorsal horn were calculated 1 h after formalin injection. The results showed that: (1) i.t. Chel significantly reduced the number of Fos-LI neurons in the dorsal horn of the spinal cord on the side ipsilateral to the formalin injection, showing a decrease by 60.3% (P<0.001) as compared to that observed in the i.t.vehicle group; (2) i.t. Nal significantly increased the number of Fos-LI neurons in the ipsilateral dorsal horn, with an increase of 46.0% (P<0.01) as compared to that in the i.t.vehicle group, the highest percentage increase being found in the deeper laminae of the dorsal horn; and (3) i.t. Chel + Nal also exhibited a significant decrease in Fos-LI neurons in the ipsilateral dorsal horn as compared to i.t. Nal group, showing a reduction of 53.2%, a value similar to that in the i.t. Chel group. These results suggest that: (1) PKC plays a role in the c-fos protein expression only in nearly one half of the Fos-LI neurons in the dorsal horn; and (2) PKC is possibly not involved in the concomitant modulation on the nociception mediated by micro- (and also partly delta-) opioid receptors in the spinal cord.

Animals↗
PubMed2004

[Effect of muscle pain on c-fos expression and NADPH-diaphorase activity in the spinal cord].

Capsaicin (Sigma, 5 mg/l ml) was unilaterally injected into dorsal neck muscles (mm. trapezius, splenius) of the cat (n = 6) anesthetized with alpha-chloralose. The laminar distribution of Fos- immunoreactive (Fos-ir) and NADPH-d-reactive neurons was studied in the sections of the cervical and lumbar segments. In comparison to sham operated animals (n = 2), 2 h after capsaicin injection the significant c-fos expression was found throughout the cervical cord (C1 - C8) ipsilaterally and lumbar cord bilaterally (L1 - L7), while the predominant mean number of Fos-ir neurons was detected in the C1 - C4 and L3-L6 segments. In cervical spinal cord, c-fos expression was three times more than in lumbar spinal cord. Dorsal neck noxious stimulation produced widespread c-fos expression in the large and small labeled cells within lamina 1, at the neck of the dorsal horn (lamina V) and also in the medial part of the intermediate zone (lamina VII) where cells of origin of the long crossed and uncrossed descending propriospinal pathways to the lumbar cord were known to be localized. The main accumulations of NADPH-d-reactive cells were registered within the marginal zone (laminae I and II) and medial part of the intermediate zone (lamina VII). Fos-ir neurons were co-distributed with NADPH-d-reactive cells within the marginal zone, and the neck of the dorsal horn, however, double-staining spinal neurons were not registered. These results strongly suggest that the revealed c-fos expression in cervical and lumbar segments depends on the activity of vanilloid receptors of the cervical muscles and confirmed the anatomical coupling of both regions through long propriospinal pathways which may be underlying in the cervico-lumbar nociceptive processing. An influence of the spino-cerebro-spinal loop on modulation c-fos expression in these regions is not excluded also.

Animals↗
PubMed2004

[Transcription of c-fos gene and DNA binding activity of transcription factor AP-1 increase upon differentiation of mouse F9 teratocarcinoma cells].

Retinoic acid (RA) causes differentiation of mouse F9 embryonic carcinoma cell line into primitive and parietal (with dibutiril-cAMP) endoderm. The role of AP-1 transcription factor during RA-induced differentiation was studied in F9 cell line. It was shown that differentiated cells acquired protein complexes, which are specifically bound to well characterized AP-1 32P-labeled binding sites from collagenase (Col-AP-1) and c-jun (Jun2-AP-1) promoters. These complexes contain c-Fos/c-Jun with Col-AP-1 site and c-Jun/ATF-2 with Jun2-AP-1 site as revealed by supershift analysis. DNA-binding activity of these complexes is high in parietal endoderm but low-detectable in undifferentiated cells. DNA-binding activity of AP-1 transcription factor correlates with increased expression of c-fos and c-jun genes. RT-PCR analysis showed an increase in steady-state level of c-fos and c-jun gene transcription at the stage of parietal endoderm (terminally differentiated F9 cells). Transcription of immediate early c-fos and c-jun genes and DNA-binding activity of c-Fos/c-Jun complex are serum dependent. The rate of c-fos and c-jun gene transcription and DNA-binding activity of c-Fos/c-Jun complex decreased in serum-starved cells, but was rapidly induced upon stimulation with serum. Undifferentiated F9 cells contain a very low level of c-fos mRNA, with may be a consequence of repressive chromatin structure in promoter region. Histone deacetylase (HDAC) activity is necessary to restrict expression of specific number of genes, also HDAC inhibitors are well known inductors of differentiation and anticancer agents. Frow cytometry analysis showed a decreased rate of proliferation of F9 cells after their incubation with HDAC inhibitors, sodium butirate and trichostatin A. Also, these ihibitors induced the transcription of c-fos gene. So, we conclude that HDAC activity may be necessary to sustain a high proliferative rate of undifferentiated F9 cells.

Animals↗
PubMed1991

Overexpression of c-fos in a human pre-B cell acute lymphocytic leukemia derived cell line, SMS-SB.

The c-fos proto-oncogene is found to be overexpressed at least 30-fold in SMS-SB, a pre-B leukemic cell line compared to other cell types. No gross alteration of the c-fos gene structure in SMS-SB cells can be detected by karyotypic or Southern analyses. C-fos in SMS-SB cells can still be induced by serum, TPA and the calcium ionophore, A23187, and superinduced by the combination of serum and cycloheximide. The elevated levels of c-fos transcripts are not due merely to an increased life span of mRNA, as the half-life of steady state c-fos mRNA in SMS-SB cells is about 40 min. Nuclear run-on transcription assays demonstrate that the transcription rate of c-fos in SMS-SB cells is up-regulated about 30-fold as compared to another pre-B leukemic cell line, NALM-6. In order to determine whether this is a cis- or transacting effect, we sequenced the 550 base pairs upstream of the SMS-SB c-fos coding region and found no mutations upstream of the mRNA CAP site. However, two point mutations at positions +23 and +98, respectively, were found in the 5' noncoding region of the first exon. Consistent with the overexpression of c-fos mRNA, the 55 kD c-fos protein is present in SMS-SB cells through detection by immunoprecipitation, but could not be detected in NALM-6 cells. SMS-SB cells however, do not appear to contain more abundant AP-1 DNA binding activity than NALM-6 cells.

Base Sequence↗
PubMed1992

Correlation of c-fos/c-jun expression with histiocytic differentiation in Hodgkin's Reed-Sternberg cells. Examination in HDLM-1 subclones with spontaneous differentiation.

The c-fos proto-oncogene, which is the normal homolog of the transforming gene carried by murine osteogenic sarcoma viruses, interacts with the protein product of another proto-oncogene, c-jun, to form a heterodimer that can recognize and bind to a specific sequence of nucleotides in the DNA. The expression of c-fos and c-jun is linked to the proliferation of certain cells and the differentiation of others, including those of monomyelocyte lineage. The authors used two cultured Hodgkin's Reed-Sternberg (H-RS) cell lines, KM-H2 and HDLM-1, and their single-cell clones to study the correlation of c-fos/c-jun expression with cell differentiation in H-RS cells. Within 48 hours after induction with phorbol ester (TPA), both parent lines exhibited markedly increased expression of c-fos/c-jun. The expression returned to the preinduction level after 96 hours, however, and the cells retained their differentiated status. The transitory increase in c-fos/c-jun expression suggests that binding of these proteins to a specific promoter in the nucleus triggers a cascade of events that result in cell differentiation. Expression of these proteins may not be required for the cells to maintain their differentiation. The authors selected three groups of sublines of HDLM-1 cells based on their degree of spontaneous cytologic differentiation. The first group, without obvious differentiation, showed a c-fos/c-jun expression pattern similar to that of the parent line. The second group, with moderate differentiation, had a high degree of expression, which decreased on treatment with TPA. The third group, which had morphologic features resembling those of histiocytes, expressed minimal amounts of c-fos/c-jun, irrespective of TPA treatment. These findings provide further evidence that c-fos/c-jun expression is related to differentiation of H-RS cells, and that these proteins are not byproducts of TPA induction. Expression of c-fos/c-jun also was noted in a subpopulation of H-RS cells in tissues; and this expression also was enhanced when these cells were treated with TPA in culture. These findings indicate that H-RS cells can differentiate to become mature-appearing cells in tissues.

Adult↗
PubMed1991

Fos is phosphorylated by p34cdc2, cAMP-dependent protein kinase and protein kinase C at multiple sites clustered within regulatory regions.

The proto-oncogene c-fos encodes a nuclear protein (Fos) that functions in transcriptional regulation in response to extracellular signals. Fos is extensively modified in the nucleus by serine and threonine phosphorylation. It has been suggested that phosphorylation may play an important role in regulating Fos function in normal and transformed cells. As a first step in addressing this issue, we have used purified Fos as a substrate for several serine-threonine protein kinases, including cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and p34cdc2. Each of these kinases phosphorylated Fos at several unique sites. These sites were located within two regions that were previously shown to reduce the transcriptional activity of Fos in vitro. Several of the sites modified in vitro were also shown to be phosphorylated in serum-stimulated fibroblasts. These findings demonstrate that Fos is a target for several protein kinases involved in signal transduction and suggest that phosphorylation could regulate the transcriptional properties of Fos.

Amino Acid Sequence↗
PubMed1990

Stimulation of adrenal medullary cells in vivo and in vitro induces expression of c-fos proto-oncogene.

The nuclear proto-oncogene, c-fos, has been implicated in the coordinated regulation of gene expression during cell proliferation and differentiation. In this study, we have demonstrated the induction of the c-fos gene products in differentiated cells of the adrenal medulla by non-mitogenic signals. Activation of adrenal medullary cells in vivo by insulin-induced hypoglycemia, and in vitro by nicotine or angiotensin resulted in the rapid and transient elevation of c-fos mRNA levels. Induction of the c-fos mRNA by angiotensin and nicotine were accompanied by the appearance of the c-fos protein. The increase in c-fos protein occurred initially in the cytoplasm and, later, in the nucleus, and it was co-localized with tyrosine hydroxylase. Nuclear expression of the c-fos protein was also induced by veratridine, forskolin and the calcium ionophore A231287. The role of calcium in the regulation of the c-fos gene by angiotensin with nifedipine and inhibition of the effects of angiotensin with nifedipine and sphingosine, a protein kinase C inhibitor. Activation of the c-fos gene may play a role in the coordinated induction of genes involved in the long-term adaptation of adrenal medullary cells to increased functional demands.

Adrenal Medulla↗
PubMed1990

Thrombin induces c-fos expression in cultured human endothelial cells by a Ca2(+)-dependent mechanism.

The proto-oncogene c-fos has been implicated in the modulation of various cell functions. We have found that thrombin, a pleiotropic activator of endothelial cells, induced c-fos mRNA in human umbilical vein endothelial cells (HEC). This effect was dose-related (0.05 to 1.0 U/mL) and transient (maximal after 1 hour and negligible within 4 hours). Since thrombin activates phosphoinositide (PI) turnover through a pertussis toxin (PT)-sensitive guanosine triphosphate-binding regulatory protein(s) (G-protein) with subsequent stimulation of protein kinase C (PKC) and Ca2+ movements, we investigated whether these intracellular pathways are also responsible for c-fos induction. PT inhibited thrombin's effect on c-fos expression, but had no effect on c-fos expression by phorbol myristate acetate (PMA). Down regulation of PKC by prolonged exposure to PMA had no effect on thrombin and ionomycin stimulation of c-fos, but inhibited PMA activation of this gene. Quenching of the Ca1(2+) increase in response to quin2 loading in the absence of external Ca2+ suppressed thrombin activity on c-fos transcription. Under the same conditions PMA activity was not inhibited or only partially inhibited. Interleukin-1 beta (IL-1 beta) and basic fibroblast growth factor (bFGF) stimulation of c-fos mRNA level were not inhibited by quin2; on the contrary, ionomycin effect was blocked by this agent. These results indicate that thrombin-induced c-fos expression in HEC does not require a fully active PKC but is dependent on normal intracellular Ca2+ availability.

Calcium↗
PubMed1990

A direct role for c-fos in AP-1-dependent gene transcription.

Transcription factor activator protein 1 (AP-1) is a protein fraction that contains c-fos, c-jun, and several other related proteins. Although this protein fraction can stimulate transcription in vitro, the relative contributions of c-fos and c-jun to the transcriptional effect of AP-1 are not clear. In order to approach this question, we have overexpressed both proteins using a baculovirus-mediated expression system and defined their DNA-binding and transcriptional enhancement activities in vitro. Gel mobility-shift and DNase 1 footprinting assays showed that c-jun protein specifically binds to DNA through an AP-1 binding site. Under the same conditions, no detectable binding of c-fos protein was observed. However, when the DNA binding assays were performed in the presence of both c-jun and c-fos, a marked increase in the affinity of c-jun for the AP-1 site was observed. An AP-1-dependent transcription assay was used to test the capability of both proteins to stimulate correctly initiated RNA synthesis in vitro. Under our conditions, c-jun protein was capable of stimulating specific RNA transcription in an AP-1 site-dependent manner. In contrast, c-fos protein showed no detectable transcriptional activation by itself. However, a transcription assay carried out in the presence of both c-fos and c-jun proteins showed that the c-fos/c-jun complex was more active as a transcriptional regulator than c-jun protein alone. These experimental results indicate that c-fos and c-jun proteins are required to reconstitute full AP-1-dependent transcriptional activation and directly demonstrate that c-fos is a regulator of gene expression.

Animals↗