SEARCH · Search PubMed

Results for “Fos”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources

PubMed2001

Light suppresses Fos expression in the shell region of the suprachiasmatic nucleus at dusk and dawn: implications for photic entrainment of circadian rhythms.

The transcription factor Fos is implicated in neuronal signaling in the suprachiasmatic nucleus, the mammalian circadian clock (Ikonomov and Stoynev, 1994; Klein et al., 1991; Kornhauser et al., 1996). Fos is expressed in two different regions within the suprachiasmatic nucleus. In the ventrolateral, retinorecipient, core region (Leak et al., 1999; Moga and Moore, 1997), Fos is induced by light and expression is closely linked, both temporally and functionally, to clock resetting and entrainment of circadian rhythms (Aronin et al., 1990; Beaulé and Amir, 1999; Hastings et al., 1995; Kornhauser et al., 1996; Kornhauser et al., 1990; Rea, 1989, 1998; Rusak et al., 1990; Wollnik et al., 1995). In the dorsomedial shell region (Leak et al., 1999), Fos expression is rhythmic (Guido et al., 1999a,b; Rusak et al., 1992; Sumova and Illnerova, 1998; Sumova et al., 1998). Expression is high during the subjective day when photic sensitivity of the core is minimal, and low in the subjective night, when photic sensitivity of the core is maximal. Although it has been shown that the pattern of Fos expression in the shell tracks the photoperiod (Sumova et al., 2000), nothing is known about whether light influences the expression of Fos in the shell region or about the role of Fos expression in the shell in clock resetting and entrainment. In the present study we found that, in rats maintained in constant darkness, brief exposure to light in the early subjective day or night induced Fos in the core, as expected, and acutely suppressed the levels of Fos immunoreactivity in the shell region. Similar changes in Fos expression in the core and shell regions were seen after exposure to a brief entraining light. Light exposure in the mid-subjective day or night differentially affected Fos expression in the core, as previously shown, but had no effect on Fos expression in the shell region. The finding that Fos expression in the shell region of the suprachiasmatic nucleus is suppressed by light at dawn and dusk suggests a critical role for the shell in photic entrainment of circadian rhythms in nocturnal rodents.

Animals↗

PubMed2000

Transient spinal cord ischemia in rat: the time course of spinal FOS protein expression and the effect of intraischemic hypothermia (27 degrees C).

1. In the present study, we characterize the time course of spinal FOS protein expression after transient noninjurious (6-min) or injurious (12-min) spinal ischemia induced by inflation of a balloon catheter placed into the descending thoracic aorta. In addition, this work examined the effects of spinal hypothermia on FOS expression induced either by ischemia or by potassium-evoked depolarization (intrathecal KCl). 2. Short-lasting (6-min) spinal ischemia evoked a transient FOS protein expression. The peak expression was seen 2 hr after reperfusion in all laminar levels in lumbosacral segments. At 4 hr of reperfusion, more selective FOS expression in spinal interneurons localized in the central part of laminae V-VII was seen. At 24 hr no significant increase in FOS protein was detected. 3. After 12 min of ischemia and 2 hr of reflow, nonspecific FOS expression was seen in both white and gray matter, predominantly in nonneuronal elements. Intrathecal KCl-induced FOS expression in spinal neurons in the dorsal horn and in the intermediate zone. Spinal hypothermia (27 degrees C) significantly suppressed FOS expression after 6 or 12 min of ischemia but not after KCl-evoked depolarization. 4. Data from the present study show that an injurious (but not noninjurious) interval of spinal ischemia evokes spinal FOS protein expression in glial cells 2 hr after reflow. The lack of neuronal FOS expression corresponds with extensive neuronal degeneration seen in this region 24 hr after reflow. Noninjurious (6-min) ischemia induced a transient, but typically neuronal FOS expression. The significant blocking effect of hypothermia (27 degrees C) on the FOS induction after ischemia but not after potassium-evoked depolarization also suggests that simple neuronal depolarization is a key trigger in FOS induction.

Animals↗

PubMed1993

The serum response element can mediate induction of c-fos by growth hormone.

The c-fos protooncogene is transcriptionally activated by a wide variety of agents including serum, growth factors, and phorbol esters. This induction is rapid and transient and is mediated through a number of identified promoter elements. Growth hormone (GH) is also known to induce transcription of c-fos in a variety of cell types including NIH 3T3 fibroblasts and 3T3-F442A preadipocytes. To identify DNA sequences in the c-fos gene regulated by GH, this study sought to determine whether induction of c-fos by GH involves previously identified c-fos promoter elements. A plasmid containing a growth factor-sensitive fragment of the upstream region of the c-fos promoter from -361 to -264 bp was tested for GH sensitivity. The fragment was cloned upstream of a human c-fos reporter [designated FOS by Human Gene Mapping 11 (1991)], which included basal promoter elements. In transiently transfected mouse NIH 3T3 fibroblasts, the promoter fragment conferred GH sensitivity on the human c-fos reporter. To identify a specific GH-sensitive DNA sequence in this promoter, a serum response element (SRE)-reporter plasmid was tested and found to be stimulated by GH. GH was effective in inducing expression through the SRE over a range of physiological GH concentrations. Since GH was recently found to synergize with serum factors in inducing c-fos transcription, the effect of GH and serum on SRE function was examined for insight into the mechanism for such synergism. The combined effect of GH and serum to induce reporter expression through the SRE was greater than the added effects of GH and serum, indicating that the synergism between GH and serum in inducing c-fos involves the SRE sequence. These studies identify the SRE as one specific DNA sequence in the c-fos promoter functionally regulated by GH. It is notable that GH is effective at physiological concentrations. Furthermore, synergism in c-fos induction between GH and serum factors is evident through the SRE.

3T3 Cells↗

PubMed2004

Effect of c-fos overexpression on development and proliferation of peritoneal B cells.

We examined effects of c-fos overexpression on the development and property of peritoneal B-1 cells using transgenic (H2-c-fos) mice carrying the c-fos gene under the control of the constitutive H-2Kb promoter. The number of B-1b cells in the peritoneal cavity of H2-c-fos mice was 4-fold larger than that in control littermates. Although the numbers of total peritoneal B cells and B-1a cells were similar between them, the peritoneal B-2 cell number in H2-c-fos mice was reduced to 50% of control littermates, suggesting the effect of c-fos overexpression on a balance of B-1b and B-2 cells in a peritoneal cavity. Adoptive transfer experiments with hematopoietic stem cells of H2-c-fos and control mice into irradiated H2-c-fos mice demonstrated that the augmentation of B-1b cells is due to the c-fos effect in B cells and the effect on environment of the peritoneal cavity of H2-c-fos mice. When peritoneal B cells were cultured with LPS in the presence or absence of IL-4, cell proliferation of B-1b cells was the highest among these peritoneal B cell subsets, and the proliferation of H2-c-fos B-1b cells was 3-fold higher than that of control B-1b cells. This augmentation is due to the c-fos effect in B cells. IgG1 production of B-1b cells in these cultures was slightly higher than those of B-1a and peritoneal B-2 cells. Thus, the c-fos overexpression augments development of B-1b cells in a peritoneal cavity and proliferation of peritoneal B-1b cells to LPS.

Adoptive Transfer↗

PubMed1993

Mating-induced FOS-like immunoreactivity in the rat forebrain: a sex comparison and a dimorphic effect of pelvic nerve transection.

Previous research has shown that mating induces the expression of the immediate-early gene, c-fos, as detected by the increased presence of nuclear FOS-like immunoreactivity (FOS-IR), in specific forebrain regions of both male and female rats. In the male both olfactory-vomeronasal (O/V) and genital/somatosensory (G/S) inputs appear to contribute to the neural FOS response to mating whereas in the female G/S input carried by the pelvic nerves appears to mediate the forebrain FOS response. To date, however, no direct sex comparison of the mating-induced forebrain FOS response has been made in rats maintained under the same steroidal conditions nor has the contribution of afferent sensory input from the pelvic nerves been assessed in males. We first compared the level of FOS-IR in brain regions of mated and unpaired gonadectomized male and female rats given 5 micrograms/kg estradiol benzoate (EB) for 7 days and 500 micrograms progesterone (P) 4 h prior to testing. One h after experiencing 1 ejaculation, both sexes showed increased FOS-IR in the medial preoptic a (MPOA), bed nucleus of the stria terminalis (BNST), medial amygdala, the ventro-lateral portion of the ventromedial nucleus of the hypothalamus (VMN), and the midbrain central tegmental field (CTF). This increase was significantly greater in the MPOA and medial amygdala of mated females than of males. Bilateral transection of the pelvic nerves significantly attenuated the increase in FOS-IR after mating in the CTF of male rats and in the MPOA, BNST, VMN, medial amygdala and CTF of females. Thus, following mating there is no sex difference in the brain regions which express c-fos, but there is a dimorphism in the contribution of afferent information conveyed by the pelvic nerves to the mating-induced FOS response. The neural FOS response of the female to mating is heavily dependent upon the G/S afferent inputs carried by the pelvic nerves whereas the male's neural c-fos response may depend on O/V input plus G/S input conveyed via other efferent pathways such as the pudendal nerves.

Animals↗

PubMed1990

Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements.

The Fos-Jun complex has been shown to activate transcription through the regulatory element known as the AP-1 binding site. We show that Fos down regulates several immediate-early genes (c-fos, Egr-1, and Egr-2) after mitogenic stimulation. Specifically, we demonstrate that the target for this repression is a sequence of the form CC(A/T)6GG, also known as a CArG box. Whereas Fos bound to the AP-1 site through a domain rich in basic amino acids and associated with Jun via a leucine zipper interaction, mutant Fos proteins lacking these structures were still capable of causing repression. Furthermore, Jun neither enhanced nor inhibited down regulation by Fos. Critical residues required for repression are located within the C-terminal 27 amino acids of c-Fos, since v-Fos and C-terminal truncations of c-Fos did not down regulate. In addition, transfer of 180 c-Fos C-terminal amino acids to Jun conferred upon it the ability to repress. Finally, Fra-1, a Fos-related protein which has striking similarity to Fos in its C-terminal 40 amino acids, also down regulated Egr-1 expression. Thus, Fos is a transcriptional regulator that can activate or repress gene expression by way of two separate functional domains that act on distinct regulatory elements.

Animals↗

PubMed2000

Prostaglandin E2-induced up-regulation of c-fos messenger ribonucleic acid is primarily mediated by 3',5'-cyclic adenosine monophosphate in MC3T3-E1 osteoblasts.

The mechanism by which the proto-oncogene, c-fos, is up-regulated in response to PGE2 in the mouse osteoblastic (MC3T3-E1) cell line was investigated using RT-PCR. c-fos messenger RNA up-regulation by dmPGE2 is rapid, starting 10 min post stimulation, and transient. The specific protein kinase A (PKA) inhibitor, H89, inhibited c-fos induction. Moreover, down-regulation of protein kinase C (PKC) activity by chronic TPA treatment had no effect on the induction of c-fos by dmPGE2. We conclude that up-regulation of c-fos by dmPGE2 is primarily dependent on PKA in MC3T3-E1 osteoblasts. In S49 lymphoma wild-type but not S49 cyc- cells, which are deficient in cAMP signaling, dmPGE2 up-regulates c-fos and increases cell growth compared with unstimulated cells. Thus in S49 lymphoma cells, c-fos induction by PGE2 is also dependent on cAMP signaling. The minimal c-fos promoter region required for dmPGE2-induced expression was identified by transfecting c-fos promoter deletion constructs coupled to the chloramphenicol acetyltransferase (CAT) reporter gene into Vero cells. Transfection of a plasmid containing 99 bp c-fos proximal promoter was sufficient to direct c-fos/CAT expression following stimulation with dmPGE2. Because induction of c-fos is mediated by cAMP, these data are consistent with activation of c-fos via the CRE/ATF cis element.

Animals↗

PubMed1991

Possible collaboration between c-fos and c-myc proto-oncogene products in in vivo lymphomagenesis.

Transgenic mice carrying the exogenous c-myc gene under regulation of the Ig enhancer (Ig-c-myc) were mated with mice carrying exogenous c-fos gene under control of the H-2Kb promoter (H2-c-fos) to examine their functional collaboration in in vivo lymphomagenesis. Two of the 33 (c-fos x c-myc) mice developed pre-B cell lymphomas within 22 weeks of age. None of the other F1 progeny expressing c-fos or c-myc alone showed malignant change within 14 months of age, suggesting that the exogenous c-fos and c-myc collaborate in in vivo lymphomagenesis. The exogenous c-myc RNA was overexpressed in the lymphomas, but the amount of exogenous c-fos RNA was not affected, suggesting that the large abundance of c-myc protein is a prerequisite for lymphoma onset or progression and c-fos protein plays a complementary role. C-fos protein induced immunodeficiency in the (c-fos x c-myc) mice like H2-c-fos mice. Natural killer cell activity of (c-fos x c-myc) mice was partially impaired. Therefore, these lymphomas may be a consequence of the synergism of two independent actions caused by the exogenous c-myc (lymphomagenesis) and the exogenous c-fos (low NK activity) in (c-fos x c-myc) mice.

Animals↗

PubMed1991

Mutagenesis of the DNA contact site in Fos protein: compatibility with the scissors grip model and requirement for transformation.

To elucidate the mechanisms involved in the transformation by fos we have initiated a study pertaining to the identification of molecular functions of Fos protein that are crucial for transformation. We have previously reported that the presence of an intact leucine zipper in Fos is an absolute requirement for the induction of transformation, but that the autorepression function of Fos is dispensable. We now show that Fos protein also needs an intact DNA (TRE)-binding site to be able to transform. Amino acid substitutions in this domain of Fos which impair DNA binding also destroy the transforming potential of Fos, suggesting that the interaction of Fos-Jun complexes with TREs may be a crucial part of Fos-induced transformation. This hypothesis is further strengthened by our observation that Fos and Jun can cooperate in the induction of transformation. We show that a Fos protein which contains a Jun leucine zipper and is thus capable of dimerization is still dependent on the presence of exogenous Jun to induce transformation. The critical positions in the Fos DNA-binding site include those which the 'scissors grip' model predicts to be crucial, although the DNA-binding site in Fos seems to extend beyond the basic region into an adjacent cluster of acidic amino acids.

Amino Acid Sequence↗

PubMed1990

Developmental expression of the Xenopus laevis fos protooncogene.

We have isolated the Xenopus laevis homologue of the protooncogene fos. Nucleotide sequence analysis of the complementary DNA revealed a coding domain for a 370-amino acid protein which shares extensive sequence homology with the avian and mammalian fos protein. During Xenopus development, the fos mRNA is present in the oocyte and egg stages and declines to relatively low levels by the mid-blastula transition. Transient expression of fos can be seen during the late neurula and again at the tadpole stage. The fos mRNA is uniformly distributed in the vegetal and animal poles of the oocytes. In a Xenopus kidney cell line, the fos gene can be transcriptionally activated by serum growth factors and 12-O-tetradecanoylphorbol-13-acetate, and the fos mRNA can be superinduced by cycloheximide. The X. laevis fos protein migrates as a series of bands around Mr 55,000 and is localized in the nucleus. Both the Xenopus fos RNA and fos proteins exhibit a short half-life analogous to that observed with their mammalian counterpart. The Xenopus fos protein readily associates with murine jun (AP-1) oncoprotein, and the complex binds efficiently to AP-1 recognition elements. Furthermore, the Xenopus fos protein collaborates with mammalian jun protein to activate transcription from 12-O-tetradecanoylphorbol-13-acetate-responsive element. The differential expression of fos during Xenopus development and its ability to regulate transcription in association with jun suggest a role during embryogenesis.

Amino Acid Sequence↗

PubMed1993

Cocaine-induced c-fos messenger RNA is inversely related to dynorphin expression in striatum.

The effects of the indirect dopamine receptor agonist cocaine in the striatum on levels of mRNAs of the immediate-early gene c-fos and the neuropeptides dynorphin, substance P, and enkephalin were analyzed with quantitative in situ hybridization histochemistry. Both single (acute) and repeated (twice a day for 4 d) systemic injections of cocaine (3.75-30 mg/kg) to rats resulted in dose-dependent, regionally specific elevations of mRNA expression in striatal neurons. A single drug treatment elevated c-fos mRNA expression, whereas repeated treatments resulted in little c-fos expression but elevated dynorphin mRNA levels. Both the regional and temporal patterns of gene expression revealed an inverse relationship between dynorphin and c-fos expression. This relationship was examined in a time course experiment in which cocaine (30 mg/kg) was administered for 1, 2, 3 or 4 d. Basal levels of dynorphin expression were relatively high in the ventral striatum, including the nucleus accumbens, a ventrolateral region, and an area along the medial bank of the striatum. A single injection of cocaine induced c-fos mRNA in striatal areas with low basal expression of dynorphin. Thus, c-fos mRNA induction was highest in the dorsal central striatum, where basal dynorphin mRNA levels were lowest. In this region, dynorphin mRNA expression increased on subsequent treatment days parallel to diminished c-fos mRNA induction. Changes in substance P. mRNA levels appeared to match directly both the temporal and regional patterns of c-fos induction. Enkephalin mRNA expression was altered, but only slightly, by these cocaine treatments. Statistical analysis of the regional patterns of basal and altered mRNA levels shows a unique inverse relationship between basal dynorphin expression and c-fos induction by cocaine. Further evidence of this relationship is provided by the dose-dependent blockade of cocaine-induced c-fos expression by spiradoline, a dynorphin agonist. Together, these results suggest that the restricted regional pattern of cocaine-induced c-fos expression is related, in part, to the basal level of dynorphin expression, and that cocaine treatment elevates dynorphin expression in striatal regions with a strong c-fos response, thereby limiting subsequent c-fos induction by cocaine. These findings lead to the hypothesis that dynorphin acts to regulate the responsiveness of striatal neurons to dopamine stimulation.

Animals↗

PubMed1993

Metrazole induces the sequential activation of c-fos, proenkephalin, and tyrosine hydroxylase gene expression in the rat adrenal gland: modulation by glucocorticoid and adrenocorticotropic hormone.

The immediate-early gene c-fos (a nuclear transcription factor) has been viewed as a nuclear "third messenger" or cellular "master switch." Both in vitro and in vivo studies have suggested that the proenkephalin (Penk) and tyrosine hydroxylase (TH) genes are potential targets of this immediate-early gene. We investigated the relationships between the activation of the c-fos gene and the activation of the Penk and TH genes in both rat hippocampus and adrenal using a commonly used model, metrazole (MTZ)-induced convulsions. The administration of MTZ produced a sequential elevation in c-fos, preproenkephalin (PPenk), and TH mRNAs. One hour after MTZ administration, c-fos mRNA was increased about 10-fold in rat hippocampus and about 5-fold in rat adrenal, without a significant change in spinal cord levels. Immunocytochemistry revealed that Fos-like immunoreactivity was greatly increased in both hippocampus and adrenal medulla at 3 hr after MTZ administration. The levels of PPenk and TH mRNAs were significantly increased (5-fold and 3-fold, respectively) in the adrenal 6 hr after MTZ treatment. The effects of MTZ on c-fos, PPenk, and TH mRNAs were dose dependent in both adrenal and hippocampus. In the adrenal, both the basal levels and the MTZ induction of PPenk mRNA were significantly attenuated by hypophysectomy (hypox) and were partially reinstated by adrenocorticotropic hormone (ACTH) replacement. In contrast, the basal levels of c-fos and TH mRNAs were not altered in hypox rat adrenal. ACTH treatment completely blocked the MTZ induction of adrenal c-fos mRNA and the subsequent induction of Fos-like immunoreactivity, whereas MTZ increased PPenk and TH mRNAs nearly 3-fold. Thus, in hypox rats MTZ can increase adrenal c-fos and TH mRNA levels without a corresponding increase in PPenk mRNA, whereas in ACTH-treated rats PPenk and TH mRNA levels in adrenal can be increased by MTZ without a preceding increase in c-fos mRNA. The MTZ induction of c-fos appears neither sufficient nor always necessary for the subsequent MTZ induction of Penk and TH gene expression. We conclude that c-fos, Penk, and TH genes can be differentially regulated in the adrenal of hypox rats or animals treated with ACTH, although they are co-localized in the same medullary cells.

Adrenal Glands↗

PubMed1993

Insulin and insulin-like growth factor I induce c-fos expression in postmitotic neurons by a protein kinase C-dependent pathway.

Recent studies indicate that insulin and insulin-like growth factors regulate development of the nervous system. The signal transduction pathways that mediate the neurotrophic responses to these peptides are largely unknown. The aims of this study were to examine the regulation of c-fos mRNA expression by insulin and insulin-like growth factor I (IGF-I) in postmitotic neurons derived from fetal chick forebrain and to investigate the role of protein kinase C (PKC) in c-fos induction by these growth factors. Cultured neurons were treated with growth factors or other known activators of c-fos gene expression, and then total cellular RNA was isolated and analyzed by Northern analysis using a full-length mouse c-fos cDNA probe. Fetal calf serum, insulin, IGF-I, 12-O-tetradecanoylphorbol (TPA), and cycloheximide induced a 2.2-kilobase c-fos transcript in neurons. Increased levels of c-fos mRNA were apparent as early as 15 min after the addition of insulin. Levels peaked after 60 min and then remained high up to 180 min. The onset of c-fos induction by IGF-I was similar to insulin; however, the response was more transient. Analyses of dose-response curves indicate that insulin and IGF-I stimulate c-fos expression by interacting with their own receptor type. The decay rate of c-fos mRNA was unaltered by insulin or IGF-I. Pretreatment of neurons with actinomycin D (2 microM) for 5 min prior to the addition of insulin completely blocked the induction of c-fos mRNA. TPA increased c-fos mRNA levels with similar kinetics to that of insulin and IGF-I; however, the attenuation phase more closely paralleled that of insulin. Two inhibitors of PKC, sphingosine and staurosporine, completely blocked the induction of c-fos mRNA by insulin, IGF-I, and TPA. These data indicate that insulin and IGF-I stimulate transcription of the c-fos gene in neurons by a PKC-mediated pathway. Increased AP-1 activity may mediate some of the neurotrophic responses to insulin and IGF-I.

Animals↗

PubMed1997

Kainic acid-induced excitotoxicity is associated with a complex c-Fos and c-Jun response which does not preclude either cell death or survival.

c-fos and c-jun mRNA induction and c-Fos and c-Jun protein expression were examined in the brains of adult rats subjected to systemic kainic acid (KA) injection at convulsant doses. Induction of c-fos and c-jun mRNA, as seen with in situ hybridization, occurred in the piriform and entorhinal cortices, neocortex, amygdala, hippocampus, dentate gyrus, and discrete thalamic nuclei. This was followed by c-Fos protein expression, as revealed with immunohistochemistry, in the same regions. However, the distribution of c-Jun protein expression differed depending on the antibody used. The distribution of cells immunostained with the antibody c-Jun (AB-1) was similar to that of c-jun mRNA, but the distribution of cells immunostained with the antibody c-Jun/AP1 (N) was restricted to a few neurons in the pyramidal cell layer of CA1 and CA3, layer II of the piriform and entorhinal cortices, basal amygdala, and discrete thalamic nuclei. Although the regional distribution of c-Fos- and c-Jun-immunoreactive cells in the hippocampus, layer II of the entorhinal and piriform cortices, basal amygdala, and discrete thalamic nuclei matched the distribution of cells committed to dying, c-Fos- and c-Jun-immunoreactive cells in the neocortex and dentate gyrus survived. Therefore, the present data show that c-fos and c-jun are not predictors of either cell death or survival, but rather, markers of cells sensitive to KA excitotoxicity. Western blots to c-Fos showed a double band at p62 in samples containing the hippocampus and entorhinal and piriform cortices (hip samples) and in samples containing the neocortex (cortex samples). The upper band was abolished following preincubation of the samples with alkaline phosphatase, thus suggesting c-Fos phosphorylation. Western blots to c-Jun (AB-1) showed a single band at about p39 in hip and cortex. However, Western blots to c-Jun/AP1 (N) identified two bands. One band at about p39 was seen in control rats and the cortex of KA-treated rats. Another band at p26 was observed only in hip samples of KA-treated rats. In addition, decreased c-Jun N-terminal kinase 1 (JNK-1) expression, as revealed on Western blots, was coincidental with the appearance of the p26 c-Jun-immunoreactive band in KA-treated rats. These results show that c-Fos and different Jun-related antigens are expressed following KA excitotoxicity, and that posttranslational modifications involving phosphorylation of c-Fos and Jun(s) may occur following KA injection. These results also stress the necessity of examining the composition of Fos and Jun-related antigens and the metabolic state of Fos and Jun(s) in different experimental models of nervous system injury.

Animals↗

PubMed1998

Induction of c-fos and c-jun mRNA expression by basic fibroblast growth factor in cultured rat Müller cells.

PURPOSE: Exogenous basic fibroblast growth factor (bFGF) induces bFGF gene expression in cultured rat Müller cells. To elucidate the mechanism that links exogenous bFGF to transcriptional regulation of bFGF gene expression in these cells, the authors examined mRNA expression of the proto-oncogenes c-fos and c-jun in response to exogenous bFGF in cultured rat Müller cells. METHODS: Müller cells from 1- to 3-day-old Sprague-Dawley rats were isolated and cultured in essential modified Eagle's medium + 10% fetal calf serum. Cultured cells were identified by immunocytochemical analysis using antibodies against vimentin, carbonic anhydrase C, and glutamine synthetase. Cells of passages 1 through 4 were treated with bFGF (0.01, 0.1, 1, 10, and 100 ng/ml), either the protein kinase C (PKC) inhibitors H-7 (30 microM) and GF109203X (1 microM) or the PKC activator phorbol 12-myristate 13-acetate (PMA; 1, 10, 100, 500 nM), and either adenylate cyclase activator forskolin (5 microM) or adenylate cyclase inhibitor SQ22536 (100 microM). Northern blot analysis was performed to determine the mRNA expression of c-fos, c-jun, and bFGF. RESULTS: Addition of bFGF to culture medium induced c-fos and c-jun mRNA expression in a dose- and time-dependent manner. Induction of c-fos mRNA was observed as early as 10 minutes (9.6-fold) after exposure to bFGF at a dose of 10 ng/ml. It reached a maximum of 17.4-fold by 30 minutes. A rapid decline of c-fos mRNA level was observed after 45 minutes of bFGF treatment. The temporal pattern of c-jun gene expression was similar to that of c-fos, whereas a maximum induction of c-jun mRNA (8.2-fold) was seen after 45 minutes of treatment. Induction of c-fos and c-jun gene expression started at a bFGF concentration of 0.1 ng/ml. It reached peak levels of 15-fold for c-fos and 7.6-fold for c-jun mRNA at 10 ng/ml. A dose-dependent upregulation of c-fos and c-jun gene expression by the PKC activator PMA was also observed. A maximum induction was seen at 100 nM PMA. The induction of c-fos and c-jun gene expression by bFGF or by PMA was blocked by the PKC inhibitors H-7 (30 microM) or GF109203X (1 microM). SQ22536 (100 microM), an adenylate cyclase inhibitor, did not inhibit bFGF-induced c-fos and c-jun gene expression, whereas forskolin (5 microM), an adenylate cyclase activator, upregulated the expression. CONCLUSIONS: These results indicate that exogenous bFGF induces c-fos and c-jun gene expression in cultured rat Müller cells through PKC activation. The proto-oncogenes c-fos and c-jun may play a role in the regulation of bFGF gene expression in response to exogenous bFGF in retinal Müller cells. These findings provide further insight into the roles of Müller cells and exogenous bFGF in protecting against photoreceptor degeneration.

Adenylyl Cyclases↗

PubMed2000

Induction of c-fos and interleukin-2 genes expression in the central nervous system following stressor stimuli.

An injection of 5% mustard in vegetable oil, an injection of vegetable oil and needle prick into a rat leg gastrocnemius muscle were selected as stressor stimuli. Expression of c-fos mRNA and interleukin-2 (IL-2) mRNA was measured using digoxigenin labeled cDNA probe. C-fos-like proteins were determined by an immunochemical method with anti-c-fos polyclonal antibodies. Thirty min after the injection of 5% mustard in vegetable oil, c-fos mRNA synthesis was shown in the sacral segments of the spinal cord. Many c-fos mRNA labeled cells were noted also in the hypothalamus (paraventricular nucleus, dorsomedial nucleus, and the lateral hypothalamic area), thalamus, hippocampus, nucleus caudatum, sensori-motor zone of the brain cortex and the amygdaloid complex. Expression of c-fos-like proteins was shown after the injection of vegetable oil and 5% mustard in vegetable oil (within 2 h) in the spinal cord structures, the maximum quantity of the labeled cells was found in the I and II sacral segments (in the superficial lamina of the gray matter of the dorsal horns in the ipsilateral side), the minimum in the IV and V lumbar segments (in the intermediate zone of the gray matter at the level of the central canal). When c-fos-like proteins expression were analyzed in the CNS, c-fos-labeled cells were detected in the same structures where c-fos mRNA was also shown. The IL-2 mRNA synthesis was shown within 2 h after the stimulus in the same brain structures as c-fos mRNA. It is always difficult to destinguish the effect of stress as sensory stimuli or as general stimuli. The c-fos immunoreactivity appeared mostly in the contralateral side of the hypothalamus, therefore maybe in our investigation the mechanism of sensory stimuli mostly results in the changes that have been obtained. The information of applied stimuli arrived in the spinal cord, and is transmitted to the brain where it activates certain brain structures inducing c-fos and IL-2 genes expression. The most important conclusion is that the used stress stimuli induced not only c-fos gene but also IL-2 gene expression in the brain. The synthesis of both mRNA takes place in the same brain structures.

Journal Article↗

PubMed1989

High invasiveness associated with augmentation of motility in a fos-transferred highly metastatic rat 3Y1 cell line.

We previously reported that v-fos transfer to a src-transformed rat 3Y1 cell line enhanced lung metastasis. To clarify the mechanism of this enhancement, we compared various biological factors related to metastatic potential between a fos-transferred highly metastatic cell line (fos-SR-3Y1-202) and the control cell line transferred with genetic marker (pSV2-neo) plus pBR322, neo-SR-3Y1-200. Lung arrest, the effect of lung extract on cell growth, or sensitivity to natural killer cells could not explain the higher metastasis of fos-SR-3Y1-202, compared to findings with neo-SR-3Y1-200. The invasiveness, assessed by penetration through a Matrigel-coated filter was about 5 times higher in fos-SR-3Y1-202 than in neo-SR-3Y1-200; high invasiveness in vitro was also observed in a fos-transferred mixed-population cell line (fos-SR-3Y1-200) and fos-transferred highly metastatic clones. Histopathological evidence of an in vivo tumor also showed the high invasiveness of fos-SR-3Y1-202 cells. To elucidate the causes of the increased invasiveness of fos-SR-3Y1-202, attachment of the cells to Matrigel and its components, such as laminin and type IV collagen, type IV collagenase activity, and motility were examined. Attachment of the cells to the substrate coated on Petri dishes or the activity of type IV collagenase did not differ significantly. On the other hand, cell motility, determined by a new method to directly quantitate alteration of cell shape continuously, using video image analysis and computer techniques, was higher in fos-SR-3Y1-202 than in neo-SR-3Y1-200. Thus, the fos-transferred cell line, fos-SR-3Y1-202 has a high invasiveness, in association with augmentation of motility, hence the enhancement of metastatic potential.

Animals↗

PubMed2005

CSF-1 induces fos gene transcription and activates the transcription factor Elk-1 in mature osteoclasts.

Mice with targeted deletion of the fos gene fail to develop mature osteoclasts, reflecting an absolute requirement for the c-Fos proto-oncogene in osteoclast precursors. C-Fos is also expressed in mature osteoclasts; however, the regulation of fos in these cells has not been studied. By using cultured murine osteoclast-like cells (OCLs) we found that treatment with colony-stimulation factor 1 (CSF-1) induced a 3.9-fold increase in c-Fos rnRNA at 30 minutes and a 2.6-fold increase at 60 minutes. With use of mature osteoclasts isolated from transgenic mice expressing the bacterial Lac-Z gene under the control of the murine fos promoter, we were able to directly demonstrate transcriptional activation of fos by CSF-1 in these cells. Transcriptional activation was 2.6-fold greater at 5 minutes and 2.8-fold greater at 15 minutes in CSF-1-treated cells than in vehicle-treated cells. CSF-1 induced nuclear protein binding to the fos serum response element that was significantly attenuated by antibodies to the transcription factor Elk-1 but not by Sap-1a. Treatment of mature osteoclasts with CSF-1 for 2 hours resulted in a significant increase in the levels of nuclear c-Fos protein. These data demonstrate that CSF-1 upregulates c-fos expression in mature osteoclasts at least in part via transcriptional activation of fos. CSF-1 induced binding of Elk-1 to the fos gene serum response element appears to be part of the molecular mechanism by which this occurs.

Animals↗