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PubMed1999

Effects of centrally administered pituitary adenylate cyclase-activating polypeptide on c-fos gene expression and heteronuclear RNA for vasopressin in rat paraventricular and supraoptic nuclei.

The effects of intracerebroventricular (i.c.v.) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) on the expression of c-fos gene as well as heteronuclear (hn) RNA for arginine vasopressin (AVP) in paraventricular (PVN) and supraoptic nuclei (SON) of rats were investigated by immunohistochemistry for c-fos protein (Fos) and in situ hybridization histochemistry for c-fos mRNA and AVP hnRNA. The i.c.v. administration of PACAP (200 pmol/rat) caused a marked induction of Fos-like immunoreactivity (LI) in PVN and SON. The nuclear Fos-LI existed in AVP-LI containing cells in the PVN and SON. The expression of the c-fos gene in the PVN and SON was increased in a dose-related manner 30 min after i.c. v. administration of PACAP. PACAP-induced expression of the c-fos gene was significantly reduced by pretreatment with a PACAP receptor antagonist, PACAP-(6-38)-NH2. In addition, Fos-LI and the expression of the c-fos gene were also observed in the periventricular region of the third ventricle after i.c.v. administration of PACAP. The induction of c-fos gene expression in the PVN and SON reached a maximum 30 min after PACAP administration. The expression of c-fos gene in the PVN and SON induced by i.c.v. administration of vasoactive intestinal peptide (200 pmol/rat) was weaker than that induced by PACAP. The hnRNA for AVP in the PVN and SON was significantly increased 30 min after i.c.v. administration of PACAP (200 pmol/rat). Our results suggest that PACAP activates PVN and SON neurons via PACAP receptors and, in parallel, transcription of the AVP gene in the PVN and SON.

Animals↗
PubMed1994

Histamine stimulates c-fos expression in hypothalamic vasopressin-, oxytocin-, and corticotropin-releasing hormone-containing neurons.

The stimulatory action of centrally administered histamine (HA) on secretion of the anterior pituitary hormones ACTH, beta-endorphin, and PRL is indirect, and previous studies have suggested that hypothalamic neurons containing CRH, arginine vasopressin (AVP), and oxytocin (OT) are involved in this response. We studied the effect of HA on neuronal activation in the hypothalamus by investigating the expression of c-fos, which is a protooncogene activated early when neurons are stimulated. The expression of c-fos was evaluated by detection of c-fos immunoreactivity (c-fos-IR) using immunohistochemistry and by measurement of c-fos mRNA using in situ hybridization techniques. In addition, the identity of the HA-stimulated neurons was investigated by dual antigen immunohistochemistry visualizing AVP-, OT-, or CRH-IR in the neurons showing increased c-fos expression. HA (270 nmol) infused intracerebroventricularly increased c-fos-IR in the hypothalamus, especially in the periventricular hypothalamic areas and certain hypothalamic nuclei, including the paraventricular nucleus (PVN) and supraoptic nucleus (SON). c-fos-immunoreactive nuclei were observed throughout the SON, whereas in the PVN, c-fos-IR was particularly pronounced in the subnuclei known to contain AVP, OT, and CRH neurons. Double labeling experiments confirmed that c-fos was expressed in AVP-, OT-, and CRH-immunoreactive as well as other neurons. In addition, HA intracerebroventricularly induced a moderate expression of c-fos-IR in the arcuate nucleus. In situ hybridization showed increased levels of c-fos mRNA in both the PVN and SON after HA infusion. We conclude that HA-induced secretion of ACTH, beta-endorphin, and PRL may be mediated via activation of hypothalamic AVP, OT, and CRH neurons.

Animals↗
PubMed1997

Cell-specific induction of c-fos expression in the pituitary gland by estrogen.

Estrogens regulate many functions of pituitary lactotrophs, including PRL gene expression, release, storage, and cellular proliferation. The mechanism by which estrogens exert such a variety of functions is poorly understood. In the uterus, estrogens rapidly and transiently induce the expression of the immediate early genes c-fos and c-jun in specific cell types. The Fos/Jun proteins form the activating protein-1 (AP1) transcription factor that mediates ligand-activated cell proliferation, differentiation, and secretion. Here we used Fischer 344 (F344) rats that develop hyperprolactinemia and prolactinomas in response to estrogens. The objectives were to: 1) determine whether estrogen induces c-fos expression in the pituitary gland and identify the responsive cells; 2) compare the dynamics of c-fos induction in the pituitary and uterus; and 3) examine the temporal relationship between c-fos expression and PRL release. Ovariectomized F344 rats were injected with 1 microg estradiol and killed at different times thereafter. Pituitaries were subjected to in situ hybridization for c-fos and immunostaining for selected pituitary cells. Estradiol stimulated c-fos expression in lactotrophs and folliculo-stellate cells within the anterior lobe without affecting either the intermediate or neural lobes. In a second experiment, c-fos messenger RNA levels were measured by solution hybridization in anterior pituitaries and uteri from estradiol-treated rats. Trunk blood was analyzed for PRL by RIA. The estrogen-induced c-fos rise in the uterus was rapid, robust, and transient, whereas that in the anterior pituitary was delayed, lower, and sustained. The profile of serum PRL levels resembles that of c-fos induction in the anterior pituitary. We conclude that: 1) both lactotrophs and folliculo-stellate cells increase c-fos expression in response to estrogens; 2) induction of c-fos expression may mediate some estrogenic effects on PRL synthesis and release and lactotroph proliferation in F344 rats; and 3) the atypical dynamics of c-fos induction in the pituitary could be due to indirect effects of estrogens on PRL-regulating factors within the hypothalamo-pituitary complex as well as to pituitary-specific estrogen receptor isoforms, coactivators, or repressors.

Animals↗
PubMed1992

D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease.

Selective agonists for D1-like and D2-like dopamine receptors can interact synergistically to enhance each other's actions on locomotion and behavior in experimental animals. Clinically, the combination of the D2 agonist bromocriptine with L-dopa (which has pronounced D1 effects) is a highly effective treatment for Parkinson's disease. The mechanisms underlying this important receptor interaction are poorly understood and are the subject of intense study in vitro. In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway, D1-selective (but not D2-selective) dopamine agonists produce a marked increase in expression of the immediate-early gene c-fos in the striatum ipsilateral to the 6-OHDA lesion. In the experiments reported here, we have used this in vivo model to explore the possibility that combinations of D1-selective and D2-selective agonists might have effects on c-fos transcription that are different from those exhibited by D1 or D2 agonists administered alone. We examined the effects of the D1-selective agonist SKF-38393 and the D2-selective agonist quinpirole (LY 171555) on the expression of Fos-like protein and c-fos mRNA in the caudoputamen and made parallel behavioral observations in the same animals. A low dose of SKF-38393 produced little contraversive rotation and little induction of Fos-like immunoreactivity in the striatum. A low dose of quinpirole elicited contralateral rotation but little or no induction of Fos-like immunoreactivity in the caudoputamen; there was, however, induction of Fos in the globus pallidus ipsilateral to the 6-OHDA lesion. Combination of the low dose of SKF-38393 and quinpirole produced a synergistic effect on rotation and elicited, in the dopamine-depleted caudoputamen, a striking pattern of Fos-like protein expression in which Fos-positive neurons were concentrated in striosomes and in the dorsolateral caudoputamen. Northern blot analysis showed that c-fos mRNA was expressed following combined agonist treatment but was not detectable after the single-agonist treatments. Both the contraversive rotation and the induction of Fos-like immunoreactivity were blocked by the preadministration of the D1-preferring antagonist SCH-23390 and the D2-selective antagonist raclopride in combination. Pretreatment with the glutamate NMDA receptor antagonist MK-801 also blocked the induction of Fos-like immunoreactivity, and it reversed the rotation. These findings suggest a D1/D2 synergistic mechanism that involves the participation of D1-responsive striatonigral and D2-responsive striatopallidal output pathways, and that is sensitive to glutamatergic modulation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Identification of an estrogen response element in the 3'-flanking region of the murine c-fos protooncogene.

We have used transient transfection assays with reporter plasmids expressing chloramphenicol acetyltransferase, linked to regions of mouse c-fos, to identify a specific estrogen response element (ERE) in this protooncogene. This element is located in the untranslated 3'-flanking region of the c-fos gene, 5 kilobases (kb) downstream from the c-fos promoter and 1.5 kb downstream of the poly(A) signal. This element confers estrogen responsiveness to chloramphenicol acetyltransferase reporters linked to both the herpes simplex virus thymidine kinase promoter and the homologous c-fos promoter. Deletion analysis localized the response element to a 200-base pair fragment which contains the element GGTCACCACAGCC that resembles the consensus ERE sequence GGTCACAGTGACC originally identified in Xenopus vitellogenin A2 gene. A synthetic 36-base pair oligodeoxynucleotide containing this c-fos sequence conferred estrogen inducibility to the thymidine kinase promoter. The corresponding sequence also induced reporter activity when present in the c-fos gene fragment 3 kb from the thymidine kinase promoter. Gel-shift experiments demonstrated that synthetic oligonucleotides containing either the consensus ERE or the c-fos element bind human estrogen receptor obtained from a yeast expression system. However, the mobility of the shifted band is faster for the fos-ERE-complex than the consensus ERE complex suggesting that the three-dimensional structure of the protein-DNA complexes is different or that other factors are differentially involved in the two reactions. When the 5'-GGTCA sequence present in the c-fos ERE is mutated to 5'-TTTCA, transcriptional activation and receptor binding activities are both lost. Mutation of the CAGCC-3' element corresponding to the second half-site of the c-fos sequence also led to the loss of receptor binding activity, suggesting that both half-sites of this element are involved in this function. The estrogen induction mediated by either the c-fos or the consensus ERE was blunted by the antiestrogen tamoxifen. Based on these studies, we believe the 3'-fos ERE sequence we have identified may be a major cis-acting element involved in the physiological regulation of the gene by estrogens in vivo.

Animals↗
PubMed1995

Cell proliferation and cell cycle progression are not impaired in fibroblasts and ES cells lacking c-Fos.

The transcription factor AP-1 is thought to play an important role in the control of cell proliferation, but the function of individual Fos and Jun family members is a largely unresolved issue. To directly analyse the function of c-Fos in the control of cell proliferation we have used embryonic stem (ES) cells and fibroblasts lacking c-Fos due to a disruption of the c-fos gene by homologous recombination. Our results demonstrate that proliferation of normally cycling cells and reentry of quiescent cells into the cell cycle following serum stimulation are not c-Fos-dependent and occur with similar efficiency in c-fos-/- and control cells. We also show that there is no compensatory overexpression or activation of other known Fos or Jun family members. On the contrary, the c-fos-/- cells showed a reduced induction of fra-1 after serum stimulation which is in agreement with the previous identification of fra-1 as a c-Fos target gene. Comparison of the AP-1 binding and transactivation activities in c-fos-/- and +/+ fibroblasts by electrophoretic mobility antibody supershift and CAT assays suggests that c-Fos is not a major component of AP-1 complexes in these cells. It is therefore conceivable that the lack of any detectable effect on cell proliferation in c-fos-/- cells might be due to a functional redundancy among the different AP-1 family members.

3T3 Cells↗
PubMed1994

Activation of a novel serine/threonine kinase that phosphorylates c-Fos upon stimulation of T and B lymphocytes via antigen and cytokine receptors.

Ligation of Ag receptors in T and B lymphocytes initiates signal transduction cascades which alter the expression of genes that regulate cellular proliferation and differentiation. The transmission of signals from the membrane to the nucleus is mediated principally through the action of protein tyrosine and serine/threonine kinases. We have identified and characterized a novel serine/threonine kinase that phosphorylated the proto-oncogene product, c-Fos, and is termed Fos kinase. Fos kinase was rapidly activated after ligation of the CD3 and CD2 receptors in Jurkat and normal human T lymphocytes and in response to IL-6 and anti-IgM in the human B cell lines AF10 and Ramos, respectively. The phorbol ester, PMA, was also a potent inducer of Fos kinase activity in all of the above populations, suggesting that PKC plays a role in the regulation of this enzyme. Fos kinase phosphorylates c-Fos at a site near the C-terminus, as well as a peptide derived from this region (residues 359-370, RKGSSSNEPSSD), and Fos peptide competitively inhibited c-Fos phosphorylation. Fos kinase was shown to be distinct from other identified serine/threonine kinases, including protein kinase A, protein kinase C, casein kinase II, MAP kinases, p70S6K and p90RSK. Fos kinase was purified by anion exchange chromatography and exhibited an apparent M(r) = 65,000 and isoelectric point = 6.1. Fos kinase may play a role in transcriptional regulation through its capacity to phosphorylate c-Fos at a site required for expression of the transcriptional transrepressive activity of this molecule. Moreover, its rapid activation suggests it may have a wider role within signal transduction cascades in lymphocytes.

Amino Acid Sequence↗
PubMed1998

Retinal ganglion cells expressing the FOS protein after light stimulation in the Syrian hamster are relatively insensitive to neonatal treatment with monosodium glutamate.

In nocturnal rodents, the c-fos gene is directly involved in the light mechanism of resetting of the suprachiasmatic nucleus (circadian clock). Light also induces c-fos expression in the retinal ganglion cell layer (GCL), but no attempt has been made to study the retinal responses to the phase-shifting effects of light. The expression of the Fos protein in each of the two populations of the GCL (displaced amacrine cells [DACs] and ganglion cells [GCs]) was analyzed in hamsters after light stimulation delivered early (circadian time [CT13]) and in the middle (CT18) of the subjective night. To evaluate as accurately as possible the number of GCs able to phase shift the locomotor activity rhythm (LAR), neonatal hamsters treated with monosodium glutamate (MSG) were also used, an in vivo model which displays retinal degeneration and LAR normally entrained by light. In nontreated hamsters, the number of Fos-immunoreactive (Fos-ir+) nuclei in the GCL was significantly higher at CT18 than at CT13. In MSG-treated hamsters, the number of Fos-ir+ nuclei was the same at both CTs and nonsignificantly different as those of nontreated hamsters at CT13. MSG treatment destroyed as many Fos-ir+ DACs as Fos-ir- DACs or Fos-ir+ GCs. Fos-ir+ GCs were less sensitive to neurotoxic than other GCs, as only 37% of them were destroyed by treatment versus 92% for Fos-ir- GCs. At CT18, a maximum of 3,500 GCs expressed Fos protein in nontreated hamsters versus only 2,200 in MSG-treated hamsters. This minor subgroup was sufficiently potent to normally synchronize the circadian rhythms to the Light/dark cycle in treated hamsters.

Animals↗
PubMed1989

Elevated c-fos expression inhibits differentiation of L6 rat myoblasts.

Expression of c-fos is induced by a number of signals in several cell systems. Although the exact function of the c-fos product is unknown, it has been implicated to be of importance for both cell growth and differentiation (Verma and Sassone-Corsi, 1987). To analyze how c-fos expression relates to in vitro myogenic differentiation, the kinetics of c-fos mRNA expression during spontaneous in vitro differentiation of L6J1 myoblasts was examined; c-fos transcripts were most abundant at day 4 of the differentiation process. Multinucleated myotubes and expression of alpha-actin and myosin heavy chain (MHC) mRNA appeared later, at day 6 or 7, and increased to maximal levels after 10 days in culture. To analyze further the relation between c-fos expression and L6J1 myogenic differentiation, L6J1 myoblasts were transfected with expression vectors containing the murine c-fos gene driven by a metallothionein promoter. The growth rate of c-fos-transfected L6J1 cells did not differ from that of control cells. However, formation of myotubes was significantly reduced in c-fos-transfected L6J1 cultures compared with neo-transfected controls. Myotube formation and expression of the myogenic markers alpha-actin and MHC were reduced in subclones expressing high levels of c-fos, but not in subclones with lower levels of c-fos expression. These results indicate that a marked elevation of c-fos expression at least partially inhibits L6J1 myogenic differentiation.

Actins↗
PubMed1986

Nerve growth factor rapidly induces c-fos mRNA in PC12 rat pheochromocytoma cells.

The nerve growth factor (NGF)-mediated increase in c-fos gene expression in the rat pheochromocytoma PC12 cell line has been investigated. NGF treatment of PC12 cells results in an increased level of c-fos mRNA within 15 min. An approximately 100-fold increase in the level of c-fos mRNA occurs 30-45 min after exposure to NGF and the c-fos mRNA concentration returns to its basal level 2 hr after NGF treatment. Thus, the half-life of this RNA transcript is extremely short. In the presence of cycloheximide, the c-fos gene is superinduced and the increased level of c-fos mRNA persists for at least 24 hr. The induction of c-fos gene expression was further studied by utilizing a monoclonal antibody (mAb-192) that is directed against the NGF receptor but does not compete with NGF for binding to the receptor. Treatment of the cells with mAb-192 inhibits the NGF-stimulated elevation of c-fos mRNA, suggesting that the antibody may interfere with the receptor's ability to generate the signal required to stimulate the transcription of this gene. NGF is not the only agent capable of inducing c-fos gene expression in these cells; epidermal growth factor, the tumor promoter phorbol 12-myristate 13-acetate, and the calcium ionophore A23187, agents that induce the c-fos gene in other cell lines, are also effective in PC12 cells. The mRNA for the nuclear protein fos is rapidly induced by NGF and other agents to which PC12 cells respond. This supports the hypothesis that the fos gene product may play a role in signal transduction.

Animals↗
PubMed1985

Viral and cellular fos proteins are complexed with a 39,000-dalton cellular protein.

The structure of viral and cellular fos gene products and their association with a 39,000-dalton cellular protein (p39) were investigated by using antisera raised against synthetic peptides. The first peptide, termed M, corresponded to amino acids 127 to 152 of the v-fos sequence, a region which is identical in c-fos. The second peptide, termed V, corresponded to the nine C-terminal amino acids of v-fos; this region is not present in c-fos. Rabbit antisera were purified by affinity chromatography against their respective peptides before being used for immunoprecipitation. M peptide antisera precipitated p55v-fos and p55c-fos, whereas V peptide antisera precipitated only p55v-fos. This observation confirms the prediction from nucleotide sequence analysis that these proteins are distinct at their C termini. p39 was precipitated in association with p55v-fos and p55c-fos by M and V peptide antisera. However, V peptide antisera did not precipitate p39 from cells expressing p55c-fos, even though the presence of p39 in such cells was demonstrated with M peptide antisera. Denaturation of cell lysates completely abolished the precipitation of p39, whereas the precipitation of p55v-fos was unaffected. Taken together, the data demonstrate that p39 exists in a complex with p55.

Amnion↗
PubMed1987

The heat shock response in HeLa cells is accompanied by elevated expression of the c-fos proto-oncogene.

Several known inducers of the heat shock response (heat stress, arsenite, and heavy metals) were shown to cause a significant elevation of c-fos mRNA in HeLa cells. Heat stress resulted in a time- and temperature-dependent prolonged elevation in the level of c-fos mRNA, which was accompanied by increased translation of c-fos protein and its appearance in the nucleus. Elevated expression of c-fos during heat stress was paralleled by induction of hsp 70 mRNA, while levels of c-myc and metallothionein mRNAs declined. Treatment of HeLa cells with arsenite or heavy metals also resulted in increased levels of hsp 70, as well as c-fos mRNA. Although elevated expression of c-fos was prevented by inhibitors of RNA synthesis, analysis of relative rates of gene transcription showed that during heat stress there was a negligible change in c-fos transcription. Therefore, the enhanced expression of c-fos during the heat shock response is likely to occur primarily through posttranscriptional processes. Cycloheximide was also shown to significantly increase the c-fos mRNA level in HeLa cells. There results are consistent with the observation that these inducers of the heat shock response, as well as cycloheximide, repress protein synthesis and suggest that the increase in the level of c-fos mRNA is caused by an inhibition of protein synthesis. This supports the hypothesis that c-fos mRNA is preferentially stabilized under conditions which induce the heat shock response, perhaps by decreased synthesis of a short-lived protein which regulates c-fos mRNA turnover.

Arsenic↗
PubMed1988

Follicle-stimulating hormone induces transient expression of the protooncogene c-fos in primary Sertoli cell cultures.

The expression of the protooncogene c-fos has been associated with the transduction of cell surface stimuli into changes in nuclear function. To evaluate the possibility that this protooncogene plays a role in the gonadotropin-dependent gene regulation, the effect of FSH on the expression of c-fos was studied in primary Sertoli cell cultures. Sertoli cells were stimulated for different time intervals with FSH and c-fos mRNA levels measured by Northern RNA blot analysis. FSH treatment increased c-fos mRNA transiently with a maximal stimulation reached in 1 h. The level of c-fos mRNA returned to basal level within 4-6 h. The induction of c-fos mRNA was dependent on the concentration of FSH used with an ED50 of 3-5 ng/ml ovine FSH-16. A similar increase in c-fos expression was induced with highly purified hFSH. The c-fos mRNA was also elevated after treatment of the Sertoli cell with (Bu)2cAMP and forskolin. (Bu)2cAMP treatment led to a sustained induction of c-fos mRNA, with increased mRNA levels being maintained after 12 h. The FSH-dependent induction of c-fos mRNA was still present in cells treated for 3 h with cycloheximide, but it was greatly reduced by actinomycin D pretreatment. These data indicate that FSH induces a transient expression of c-fos in cultured Sertoli cells. This induction is probably mediated by cAMP and likely involves an increased transcription of the c-fos gene. Early expression of this gene might be an intermediate step required for gonadotropin-dependent regulation of expression of other genes.

Animals↗
PubMed1985

Transient induction of c-fos and c-myc in an immediate consequence of growth factor stimulation.

Treatment of serum-deprived fibroblasts with serum or growth factors results in an immediate induction of the c-fos and c-myc proto-oncogenes. Maximal levels of c-fos mRNA are detected 30 minutes after treatment and maximal levels of c-myc mRNA are detected 60 minutes after treatment. The c-fos protein is expressed at high levels for about two hours following induction, yet the cell morphology remains normal. Thus, either an extended period of c-fos expression is required for cellular transformation, or the highly modified form of the fos protein, present in stimulated cells, is biochemically different from the transforming protein and is therefore not capable of inducing transformation. In this system, growth factor treatment results in mitogenesis. However, c-fos and c-myc are also induced in A431 cells, and in subclones derived from A431 cells, treated with epidermal growth factor (EGF). No correlation was found between the effects of EGF on A431 cell proliferation and the induction of c-fos and c-myc. Interestingly, the strongest inducer of c-fos in A431 cells was the calcium ionophore A23187. Induction occurred in almost 100% of the treated cells without prior serum deprivation or growth arrest. Treatment of HL60 cells with 12-0 tetra decanoylphorbol-13-acetate (TPA), which promotes macrophage-like differentiation, also induced c-fos with a time course similar to that observed in mitogen-treated fibroblasts. Thus, in HL60 cells, c-fos induction is associated with differentiation. In normal macrophages c-fos and c-myc can also be induced by CSF-1. However, the kinetics of induction are entirely different from those in growth factor-stimulated fibroblasts. Taken together, the data suggest a more general role for c-fos and c-myc in the transduction of growth factor signals received at the cell membrane, within the nucleus.

Animals↗
PubMed1999

Persistent Fos protein expression after orofacial deep or cutaneous tissue inflammation in rats: implications for persistent orofacial pain.

This study was designed to systematically examine the effects of persistent orofacial tissue injury on prolonged neuronal activation in the trigeminal nociceptive pathways by directly comparing the effects of orofacial deep vs. cutaneous tissue inflammation on brainstem Fos protein expression, a marker of neuronal activation. Complete Freund's adjuvant (CFA) was injected unilaterally into the rat temporomandibular joint (TMJ) or perioral (PO) skin to produce inflammation in deep or cutaneous tissues, respectively. Rats were perfused 2 hours, 24 hours, 3 days, or 10 days following CFA injection. The TMJ and PO inflammation-induced Fos expression paralleled the intensity and course of inflammation over the 10-day observation period, suggesting that the increase in intensities and persistence of Fos protein expression may be associated with a maintained increase in peripheral input. Compared to PO CFA injection, the injection of CFA into the TMJ produced a significantly stronger inflammation associated with a greater Fos expression. In TMJ- but not in PO-inflamed rats, Fos-like immunoreactivity (LI) spread from superficial to deep upper cervical dorsal horn as the inflammation persisted and there was a dominant ipsilateral Fos-labeling in the paratrigeminal nucleus. Common to TMJ and PO inflammation, Fos-LI was induced in the trigeminal subnuclei interpolaris and caudalis, C1-2 dorsal horn, and other medullary nuclei. Substantial bilateral Fos-LI was found in the interpolaris-caudalis trigeminal transition zone. Further analysis revealed that Fos-LI in the ventral transition zone was equivalent bilaterally, whereas Fos-LI in the dorsal transition zone was predominantly ipsilateral to the inflammation. The differential induction of Fos expression suggests that an increase in TMJ C-fiber input after inflammation and robust central neuronal hyperexcitability contribute to persistent pain associated with temporomandibular disorders.

Animals↗
PubMed1995

Selective expression of fos- and jun-related genes during osteoblast proliferation and differentiation.

Developmental studies of oncogene expression and transgenic animal studies implicate c-fos and other fos and jun family members in the regulation of bone tissue formation. Therefore, to initiate experimental examination of the hypothesis that expression of fos- and jun-related genes is functionally coupled to modulation of gene expression which supports bone development, we determined levels of expression of the principle fos and jun family members during progressive differentiation of normal rat calvaria-derived osteoblasts within two contexts. First, cellular mRNA levels were quantitated under conditions where expression of serum-induced early response genes had returned to basal levels. Our findings demonstrate high levels of c-fos, c-jun, and jun B mRNA transcripts during the proliferative period of osteoblast development, while expression of fra-1 and fra-2 is enhanced during the differentiation period. jun D is constitutively expressed during the time course exhibiting only a 30% decline in levels postproliferatively, and fos B mRNA is undetectable by Northern blot analyses. Late in the developmental sequence, apoptosis is evident. At this time, fra-1 expression is completely downregulated, while c-fos, fra-2, c-jun, jun B, and jun D show a dramatic enhancement in expression. Second, we addressed differential expression of fos and jun family members in relation to serum responsiveness as a function of stages of phenotypic development. Proliferating cells exhibit a prolonged induction of fos and jun family members in response to serum. While in differentiated cells, which are refractory to growth stimulus even when exposed to fresh serum every 2 days, a spike in fos and jun expression is observed. Thus, our data demonstrate significant differences in basal and serum responsiveness of fos and jun family members over the course of osteoblast differentiation. These findings are consistent with multiple lines of evidence linking activity of these early response genes to regulation of cell growth and development of the bone tissue phenotype.

Animals↗
PubMed1993

Expression of c-fos and related genes in the rat heart in response to norepinephrine.

We have investigated the cellular and regional localization of Fos-like immunoreactivity (FLI) in the rat heart in response to the hypertrophic hormone norepinephrine (NE). Previous studies have demonstrated elevated c-fos mRNA levels in the rat heart following this treatment but have not shown which cell type(s) or specific chamber(s) of the heart contribute to the response in vivo, or whether Fos protein is actually produced. Administration of a single injection of NE (2.5 mg/kg) or chronic infusion of NE (100 micrograms/kg/h) led to an increase in Fos-like immunoreactivity in the nuclei of cardiac myocytes and vascular smooth muscle cells compared to control tissue. The response was transient with maximal immunoreactivity observed 2-3h following treatment, falling to near basal levels in most regions of the heart after 6 h. Although all chambers of the heart contributed to the response, greatest Fos-like immunoreactivity was observed in the left atrium and left ventricle, with intermediate levels found in the septum and right ventricle, and lowest levels in the right atrium. Fos-like immunoreactivity observed in the left atrium was accompanied by elevated mRNA levels of fra-1 and fra-2 but not c-fos itself indicating that a related gene product other than Fos contributed to the observed response. Experiments with the Langendorff perfused rat heart showed that NE and elevated perfusion pressure independently increased both c-fos mRNA and FLI. This work is the first evidence for a direct action of NE on Fos expression in adult, as opposed to neonatal, cardiomyocytes. These results lend further support to the notion that Fos and related gene products mediate some of the hypertrophic actions of norepinephrine.

Animals↗
PubMed1998

C-fos mediates cocaine inhibition of NGF-induced PC12 cell differentiation.

In utero cocaine exposure can affect CNS development. Previous studies showed that cocaine inhibits neuronal differentiation in a dose-dependent fashion, in nerve growth factor (NGF)-stimulated PC12 cells, without affecting cell viability. NGF activates intracellular signaling proteins, specific immediate-early genes (IEG) including a transient peak of c-fos expression, and induction of late genes expression, leading to the neuronal phenotype. We hypothesized that cocaine interferes with NGF signaling. Therefore, we examined the pattern of c-fos expression in our cellular model. Time course of c-fos expression up to 72 h was determined in cells treated with NGF 20 ng/ml and cocaine 10 microgram/ml (a moderately toxic level) by RT-PCR analysis. Total RNA was isolated from cells, and levels of c-fos mRNA were estimated using gene-specific primers. In both control and experimental conditions, c-fos level was maximal at 0.5 h. In the control cells, c-fos expression declined rapidly to less than 5% of the 0.5h value, while in the cocaine-treated cells, c-fos level persisted through the 72-h exposure. Adding c-fos antisense to cells treated with NGF and cocaine resulted in significant improvement of neurite out-growth, from 28% (NGF + cocaine) to 89% (NGF + cocaine + c-fos antisense) of control differentiation after 72 h of exposure (Dunnet's T < 3.24). Inhibitory effects of cocaine on NGF-induced PC12 differentiation may be attributed to alteration of c-fos expression. Further studies will be required to examine the role of D1 receptor activation in mediating c-fos expression and to explore the effects of cocaine on other IEGs.

Animals↗