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PubMed1996

c-fos mRNA and FOS protein expression is induced by Ca2+ influx in GH3B6 pituitary cells.

The expression of the immediate early gene c-fos was studied at the mRNA and the protein level in cells of the pituitary tumour cell line GH3B6. The induction of c-fos mRNA as detected by Northern blot analysis was stimulated by TRH and by depolarization with KCl, both leading to a rise in cytosolic free [Ca2+] ([Ca2+]i), and also by epidermal growth factor (EGF). To assess the role of the changes in [Ca2+]i in the induction of c-fos, Ca2+ was chelated in the extracellular medium with EGTA to prohibit Ca2+ influx during stimulation, or intracellular Ca2+ stores were emptied by prolonged exposure to EGTA, a treatment which abolished all [Ca2+]i changes. In the latter case, the effect of TRH on c-fos mRNA expression was almost completely abolished, whereas EGF still caused substantial c-fos induction. Full induction of c-fos mRNA by TRH required a prolonged phase of stimulated Ca2+ influx. c-fos mRNA induction by TRH and KCl was markedly inhibited by two blockers of Ca2+/calmodulin-dependent protein kinase (CaM kinase), KN-62 and calmidazolium. In contrast, KCl induction of c-fos and the effects of KN-62 on TRH induction of c-fos were not observed in a closely related pituitary line GH4C1 in which TRH exerts its effects on immediate early genes predominantly via the protein kinase C pathway. In GH3B6 cells stimulated with TRH or KCl, enhanced FOS protein levels were detected by immunofluorescence and localized in the nucleus with confocal microscopy. Analysis by immunoblotting showed that TRH induced two protein species with apparent molecular masses of 52 and 57 kDa. In GH3B6 cells stimulated with KCl or TRH, the 52 kDa species was mainly found whereas, in the GH4C1 cells, TRH predominantly stimulated the 57 kDa species. These data show that distinct signalling pathways (CaM kinase and protein kinase C) involve Ca2+ influx to induce the transcription of the early gene c-fos, and that the resulting FOS protein species may depend on the pathways involved.

Analysis of Variance↗
PubMedDate not supplied

In vivo effects of adrenocorticotropin on c-jun, jun-B, c-fos and fos-B in rat adrenal.

We have studied the in vivo effects of adrenocorticotropin (ACTH) on mRNA levels of c-jun, jun-B, c-fos and fos-B, in rat adrenals. In control rats, c-jun mRNA was abundant in both zona glomerulosa (ZG) and zona fasciculatareticularis (ZF-R). Although less abundant than c-jun, the mRNA of jun-B could be detected in both zones, whereas that of c-fos could barely be detected and that of fos-B could not. After an injection with short acting ACTH, mRNA levels of c-jun, c-fos, jun-B and fos-B were maximally increased in both zones within 30 min. Within 5h, the mRNA levels decreased towards control levels for c-jun, to below control levels for jun-B, and to undetectable levels for c-fos and fos-B. After a sustained stimulation by two daily administrations of long acting ACTH, the mRNA of c-jun was still abundant in both zones, although its level decreased by 50% and 80% after 36h and 9 days, respectively, after the first injection. Under such conditions, the mRNA level of jun-B was increased, that of fos-B could barely be detected, and that of c-fos could not be detected. To conclude, these results suggest that jun-B, fos-B, and also c-fos play a role in triggering early events leading to an increased steroidogenesis, as well as a basic role in maintaining the integrity of the adrenal cortex in the case of c-jun and jun-B.

Adrenal Glands↗
PubMed1996

c-Fos expression in the rat intergeniculate leaflet: photic regulation, co-localization with Fos-B, and cellular identification.

Ambient light alters the level of the transcriptional regulatory protein c-Fos in the suprachiasmatic nucleus, the site of an endogenous circadian clock in mammals, and in one other retino-recipient area, the intergeniculate leaflet of the lateral geniculate complex. Complementing previous work by ourselves and others on the photic and temporal regulation of c-Fos expression in the suprachiasmatic nucleus, the present studies investigated c-Fos regulation in the rat intergeniculate leaflet, revealing some important differences between the two brain regions. In the intergeniculate leaflet, the levels of c-fos mRNA (by in situ hybridization) and immunoreactive c-Fos protein (by immunohistochemistry) were elevated by light pulses administered either during the subjective day or subjective night. The regulation of immunoreactive Fos-B protein was similar to c-Fos, and 98% of Fos-B-expressing cells were also c-Fos-positive (by double-label immunofluorescence). By combining c-Fos immunofluorescence with stereotaxic injections of the retrograde tract tracer FluoroGold, we found photically-induced c-Fos in 15% of intergeniculate leaflet neurons projecting to the suprachiasmatic nucleus and in 34% of those projecting to the contralateral intergeniculate leaflet. Intergeniculate leaflet cells that express c-Fos after photic stimulation appear to represent a functionally-defined population that does not correspond to anatomically-defined categories based on connectivity or peptidergic phenotype.

Animals↗
PubMed1999

Suppression of post-ischemic-induced fos protein expression by an antisense oligonucleotide to c-fos mRNA leads to increased tissue damage.

Activation of c-fos, an immediate early gene, and the subsequent upregulation of Fos protein expression occur following neural injury, including focal cerebral ischemia (fci). Fos and Jun form a heterodimer known as activator protein 1, which regulates the expression of many late effector genes. To study the downstream effects of c-fos expression following ischemia, we suppressed the translation of c-fos by administering an antisense oligonucleotide (AO) to c-fos mRNA. Eighteen hours prior to fci, male, Long Evans (LE) rats received intraventricular injections of AO, mismatched AO (MS) or artificial cerebrospinal fluid (aCSF). Fci was induced by permanent right middle cerebral artery occlusion. At 24-h post-occlusion, neurological function was assessed, and the animals were sacrificed. The brains were removed and stained with triphenyltetrazolium chloride for infarct volume determination. Fos immunohistochemistry was performed in separate animals to determine the effects of treatment on Fos expression number of Fos positive cells. AO administration reduced the number of cells with fci-induced Fos expression by approximately 75%. No differences in neurological scores existed between any of the groups. AO-treated LE developed larger infarcts (40.1+/-1.0%, mean+/-S.D., p<0.001) than MS- or aCSF-treated controls (34.3+/-1.0%, 34.6+/-1.0%, respectively). These results suggest that c-fos activation and subsequent Fos protein expression exerts a neuroprotective effect, which is likely via upregulation of neurotrophins, following focal cerebral ischemia. This response, among others, may contribute to brain adaptation to injury that underlies functional recovery after stroke.

Animals↗
PubMed1988

Activation of the transforming potential of the human fos proto-oncogene requires message stabilization and results in increased amounts of partially modified fos protein.

The requirements for activation of the transformation potential of the human c-fos proto-oncogene were investigated. Recombinant plasmids containing the Moloney murine leukemia virus long terminal repeat directing transcription of the c-fos coding region and either the authentic c-fos 3' untranslated region (UTR) or the 3' UTR from human c-myc were inefficient at inducing transformation. In contrast, a recombinant that substituted most of the c-fos 3' UTR with the 3' portion of the simian virus 40 T-antigen gene transformed cells well. This difference in transformation efficiency appeared to be due to significantly higher levels of fos mRNA and protein expressed from the transforming recombinant. This, in turn, was due to the much greater stability of its mRNA compared with those from the poorly transforming recombinants containing the c-fos or c-myc 3' UTR. Thus, the 3' UTR of the human c-fos mRNA is responsible for its rapid degradation and limits the steady-state levels of transcript and protein. Cells transformed by the activated human c-fos plasmids contained increased amounts of partially modified c-fos protein (c-Fos). This form of c-Fos turned over much more rapidly than the highly modified form of c-Fos induced by serum stimulation.

Animals↗
PubMed1988

Growth factors regulate transin gene expression by c-fos-dependent and c-fos-independent pathways.

The rapid induction of the proto-oncogene c-fos by growth factors and other bioactive agents, and the recent evidence that the c-fos protein (Fos) is associated with transcriptional complexes, suggests that Fos may represent an integral part of an intracellular messenger pathway that triggers changes in gene expression and ultimately phenotypic alterations. This report examines the role of c-fos in growth factor stimulation of transin, a matrix-degrading secreted metalloproteinase. Platelet-derived growth factor (PDGF) stimulation of transin RNA was blocked by a selective reduction in Fos synthesis with antisense c-fos mRNA, whereas epidermal growth factor (EGF) stimulation of transin occurred despite an equivalent inhibition of Fos levels. The stimulatory effect of both PDGF and EGF on transin transcription involved factors recognizing the sequence TGAGTCA, which is found in the transin promoter and is reported to be a binding site for the transcriptional factor Jun/AP-1 and for associated Fos and Fos-related complexes. Thus both Fos-dependent and Fos-independent pathways exist for growth factor regulation of gene expression, and both effects may be mediated through the same cis-acting transcription element.

Animals↗
PubMed2003

c-Fos but not v-Fos protein induces programmed cell death of v-myb-transformed monoblasts.

c-Fos and v-Fos belong to a group of proteins forming the transcription factor AP-1 that is important for regulation of proliferation, differentiation and programmed cell death in multiple cell types. In this study, we examined the role of c-Fos and v-Fos proteins in v-myb-transformed BM2 monoblasts. We show that while the v-Fos protein prolongs the G0G1 phase of the BM2 cell cycle, c-Fos leaves the cell cycle unaffected and, rather, induces programmed cell death. The apoptosis-promoting activity of the c-Fos protein is markedly enhanced in cells cultivated under serum-free conditions. c-Fos-induced apoptosis of BM2 cells occurred in the presence of Bcl-2 and was not dependent on the transcription activation function of the c-Fos protein. No differentiation-promoting activity of the Fos proteins was observed. The effects of Fos proteins on BM2 cells differ from those induced by Jun proteins, suggesting differential roles of individual components of the AP-1 transcription factor in regulation of essential cellular processes.

Animals↗
PubMed1996

Regulation of c-Fos mRNA and fos protein expression in olfactory bulbs from unilaterally odor-deprived adult mice.

Odorant deprivation, produced by unilateral naris closure, profoundly reduces tyrosine hydroxylase (TH) expression within intrinsic olfactory bulb dopamine neurons. The TH gene contains an AP-1 site, which interacts with the product of the immediate early gene, c-fos. c-Fos exhibits activity dependent regulation in the CNS. The hypothesis that odorant stimulation and deprivation might modify c-fos expression in TH neurons was tested in adult CD-1 mice, subjected to unilateral naris closure. After 2 months, naris closed and control mice were exposed to either clean air for 60 min or clean air for 60 min followed by 30 min of alternating exposure to 10% isoamyl acetate (1 min) and air (4 min). A parallel reduction occurred in TH and fos expression (both c-fos mRNA and fos-like immunoreactivity) in the glomerular layer of the odorant-deprived olfactory bulb. Odor stimulation induced a short-lived increase in c-fos mRNA and fos-like immunoreactivity in olfactory bulbs contralateral to naris closure. The increase in fos expression was region-specific in the glomerular layer but more diffuse in mitral and granule cell layers. In olfactory bulbs ipsilateral to naris closure, odor stimulation also induced c-fos mRNA expression in the mitral and granule cell layers and sparsely within limited periglomerular regions. Odor induced expression in mitral and granule cell layers may represent increased centrifugal activity acting on as yet unknown genes. These results suggest a correlation between c-fos mRNA expression and increased neuronal activity in the olfactory bulb which, in turn, acts to regulate TH expression in periglomerular neurons.

Animals↗
PubMed1995

Fos proteins can act as negative regulators of cell growth independently of the fos transforming pathway.

The proto-oncogene c-fos is known to be an important positive regulator of cell growth and notably of the G0/G1 transition. However, we observed that v-fos or c-fos-transformed rat-1 fibroblasts paradoxically had a low growth rate as compared to control untransformed rat-1 cells. We determined that this slow growth mainly reflects an increase of the G1 phase of the cell cycle (up to fourfold). In addition, the G0 --> S progression of serum-starved fos-expressing rat-1 cells refed with serum was found to be also delayed as compared to rat-1 cells. The delayed G0 --> S progression in fos-expressing cells was accompanied by the inappropriate levels or kinetics of expression of several cell cycle-regulated genes (cyclin D1, cdc2, cdk2, cdk4 and rb). Furthermore, a clear uncoupling of the pRb hyperphosphorylation with the entry into S phase was found in these fos-expressing rat-1 cells. Interestingly, the effect of the Fos proteins on the cell cycle was independent of the fos transforming pathway, indicating that the effector genes for Fos proteins are likely to be different for each process. In conclusion, our results indicate that Fos proteins may act as negative regulators of cell growth in some cell types, independently of the fos transforming pathway.

Animals↗
PubMed2003

Role of the Fos family members, c-Fos, Fra-1 and Fra-2, in the regulation of cell motility.

The AP-1 transcription factor is composed of members of the Fos, Jun and ATF families, and plays a key role in tumor progression. We investigated whether Fos proteins regulate cell motility, and if so, whether this capacity is related to their transactivation potential. Two cell lines with different expression profiles of AP-1 were employed focusing on the Fos-family members c-Fos, Fra-1 and Fra-2. Transactivation motifs are found in c-Fos, but not in Fra-1 or Fra-2. The adenocarcinoma CSML0 cells display a low motility and do not express Fra-1 or Fra-2, and only very little c-Fos. In contrast, the fibroblastoid L929 cells express both Fra-1 and Fra-2, but no c-Fos, and these cells display a high motility. Transfection with Fra-1 or c-Fos, but not with Fra-2, strongly enhanced the motility of CSML0 cells. The effect of Fra-1 required the presence of the N-terminal domain of this protein. Conversely, transfection with a Fos dominant-negative mutant or with anti-sense fra-1 or fra-2, strongly reduced the motility of L929 cells. Changes in cell motility correlated with the morphological appearance and the degree of contact with the substratum. We conclude that Fos proteins have distinct roles in the regulation of cell motility.

Animals↗
PubMed1993

Developmental regulation of Fos and Fos-related antigens in cerebral cortex, striatum, hippocampus, and cerebellum of the rat.

Previous work has associated the proto-oncogene c-fos with such events as neuronal excitation and cell growth and differentiation. This study specifically examined the expression of the Fos protein as well as other Fos-related antigens (Fras) during postnatal development of rat brain. Ages P1 through P15 as well as adult animals (P60) were examined. Particular focus was placed on developing cerebral cortex, striatum, hippocampus, and cerebellum. We used both the Alu antiserum, which recognizes the Fos protein specifically, and the M5 antiserum, which recognizes both Fos and a family of Fos-related antigens. Fos and Fras were developmentally regulated in a region- and cell-specific manner. Differential nuclear and cytoplasmic labeling appeared age dependent. Transient Fos expression was generally followed by a more protracted time course of Fra expression. Fos and a delayed or an extended expression of Fras were observed in subplate neurons between P1 and P15, in striatal striosome and matrix neurons between P1 and P9, and in hippocampal pyramidal neurons between P1 and P9. Fras alone were expressed in cerebral cortex pyramidal neurons and other cortical neurons between ages P1 and P15. Fos and Fras were concomitantly expressed in piriform and entorhinal cortical neurons between P1 and P9 and in cerebellar Purkinje cells between ages P5 and P10. Constitutive levels of Fos and Fras remained detectable in adult animals in a subset of cerebral cortical neurons and cerebellar Purkinje neurons.

Animals↗
PubMed1994

Targeted disruption of the c-fos gene demonstrates c-fos-dependent and -independent pathways for gene expression stimulated by growth factors or oncogenes.

The c-fos proto-oncogene is believed to play a pivotal role in transducing growth factor-mediated signals from the extracellular milieu into the nucleus. c-fos protein dimerizes with c-jun and related proteins and mediates transcription via AP-1 sites. Using c-fos-deficient mice generated through gene knockout techniques, we derived 3T3-type cell lines from primary embryonic fibroblasts. The c-fos-deficient cells grow normally under optimal culture conditions and show only a slight reduction in growth rate in low serum culture compared with control cells. They also express mRNA for most of the Fos and Jun family members at normal levels. The overall levels of AP-1 DNA binding activity are normal and several genes (c-jun, MCP1, metallothionein) known to contain functional AP-1 sites are expressed normally in the c-fos-deficient and control cells. In contrast, mRNA for the metalloproteases stromelysin (MMP-3) and type I collagenase (MMP-1), which are often induced by oncogenes and growth factors and have been implicated in tumor invasiveness, cannot be induced by epidermal growth factor or platelet-derived growth factor in c-fos-deficient cells. Transformation of mutant cells with polyoma middle T oncogene essentially restores wild-type levels of stromelysin expression, while transformation with v-src leads to only a weak induction of the metalloprotease. These results clearly demonstrate that some AP-1-dependent genes require c-fos for full expression while others do not; oncogenes may activate expression of metalloproteases via either fos-dependent or fos-independent mechanisms. These results also imply that c-fos may play an important regulatory role in the invasive behavior of malignant tumors, independent of any role this proto-oncogene might play in cell growth per se.

3T3 Cells↗
PubMed1995

Expression of c-fos mRNA after cortical ablation in rat brain is modulated by basic fibroblast growth factor (bFGF) and the NMDA receptor is involved in c-fos expression.

Expression of c-fos mRNA after cortical injury was studied using the in situ hybridization technique. Strong signals for c-fos mRNA were observed immediately after cortical ablation in neurons throughout the cortex ipsilateral to the injury. However, this c-fos mRNA expression was transient and disappeared within 6 h after the injury. When basic fibroblast growth factor (bFGF; 1 micrograms) was applied to the site of ablation, c-fos mRNA signals were observed for a much longer period. Even 24 h after injury, diffuse expression of c-fos mRNA was detected throughout the cortex, being mainly confined to non-neuronal cells. Intraperitoneal injection of MK-801 (3 mg/kg), a non-competitive NMDA receptor antagonist, suppressed the expression of c-fos mRNA after cortical ablation. It suppressed both the immediate and late expression induced by cortical ablation and bFGF. The immediate expression of c-fos in neurons is likely to be due to spreading depression, while neuronal-glial interactions would be involved in the mechanism of late c-fos expression by non-neuronal cells. Our results suggest that induction of c-fos after cortical injury can be modulated by topically applied bFGF and that the N-methyl-D-aspartate (NMDA) receptor is involved in c-fos expression not only caused by injury itself but also induced by injury and bFGF. As the immediate early genes regulate secondary gene responses, the induction of c-fos may contribute to neuronal plasticity and bFGF may enhance its effect.

Animals↗
PubMed1994

Utilization of a fos-lacZ plasmid to investigate the activation of c-fos during cellular senescence and okadaic acid-induced apoptosis.

C-fos is an immediate-early gene that is induced by external stimuli and is possibly involved in initiation of DNA synthesis by such stimuli. In these studies, we used the murine c-fos promoter coupled to a lacZ reporter gene to study fos induction in senescent and quiescent cells. In transfected, quiescent, immortal Syrian hamster embryo (SHE) cells (10W), serum stimulation induced the expression of the fos construct to the same extent that DNA synthesis was stimulated. In contrast, in transfected normal cells that have a finite life span, we observed that the cells failed to display upregulation of fos-lacZ in response to serum in individual cells as they senesced. High doses of the phosphatase inhibitor okadaic acid (160-1000 nM) also induced fos-lacZ expression in quiescent immortal cells; however, induction of DNA synthesis and expression of fos-lacZ were not coordinately induced as a function of okadaic acid concentration. Low concentrations of okadaic acid (0.16 nM) induced DNA synthesis but not fos-lacZ expression, indicating that induction of DNA synthesis by phosphatase inhibitors may bypass, at least quantitatively, the requirement for c-fos induction. At the levels of okadaic acid that induced fos-lacZ expression, cell death, rather than DNA synthesis, was observed. The cells died by apoptosis, thereby implicating a signaling pathway that includes c-fos induction in this process.

Animals↗
PubMed1994

Insulin stimulates phosphorylation of c-Jun, c-Fos, and Fos-related proteins in cultured adipocytes.

In differentiated 3T3-F442A adipocytes, insulin stimulated rapid and transient phosphorylation of c-Jun. Insulin also stimulated phosphorylation of c-Fos and several Fos-related proteins (pp72, pp45, and pp39) as indicated by precipitation with anti-c-Fos antibody following exposure to denaturating conditions. Phosphorylation of c-Fos was stimulated by 7-fold by 60 min, while phosphorylation of Fos-related proteins reached maxima of 3.5-5.5-fold at 15 to 60 min. The increase in phosphorylated c-Fos was due to an increase in both c-Fos protein and the stoichiometry of c-Fos phosphorylation, and was not observed in c-fos (-/-) cells. Additionally, insulin stimulated phosphorylation of a protein with molecular mass of approximately 82 kDa on tyrosine residues by 2.5-fold within 30 min; this protein appeared to be immunologically related to c-Fos. These increases in the phosphorylation of AP-1 transcription factors correlated with a > 5-fold stimulation of expression of a 12-O-tetradecanoylphorbol-13-acetate-responsive element-chloramphenicol acetyltransferase reporter gene transiently transfected into 3T3-F442A cells. These results indicate that insulin stimulates the phosphorylation of AP-1 transcription factors and several Fos-related proteins on serine and tyrosine residues. This is associated with changes in AP-1-mediated gene expression in vivo, suggesting that AP-1 phosphorylation by insulin plays a role in insulin-regulated gene expression.

3T3 Cells↗
PubMed1983

Analysis of FBJ-MuSV provirus and c-fos (mouse) gene reveals that viral and cellular fos gene products have different carboxy termini.

The complete nucleotide sequence of the FBJ-MuSV proviral DNA and the cellular homolog (c-fos) of its oncogene (v-fos) have been determined. The 4026 nucleotide long FBJ-MuSV proviral DNA contains two long terminal repeats, a substitution of 1639 nucleotides of mouse cellular DNA (v-fos) and the 3' end of the env gene derived from FBJ-MuLV. The sequences of the parental FBJ-MuLV and the cellular c-fos (mouse) gene share five of five nucleotides at the 5' end and ten of 11 nucleotides at the 3' end of the v-fos substitution. When compared with the v-fos sequences, the c-fos gene contains four discontinuous regions, three of which are flanked by sequences characteristic of introns. Direct sequence analysis of c-fos (mouse) RNA by primer extension demonstrates that the fourth discontinuity is due to a 104 bp deletion in the v-fos gene. As a consequence of the deletion, the predicted v-fos and c-fos gene products differ at their C termini.

Amino Acid Sequence↗
PubMed1987

Analysis of Fos protein complexes and Fos-related antigens by high-resolution two-dimensional gel electrophoresis.

Protein complexes containing the c-fos protein (Fos) and (Fos)-related antigens were isolated from serum-stimulated fibroblasts and from nerve growth factor plus benzodiazepine-treated pheochromocytoma (PC12) cells, and investigated by high-resolution two-dimensional gel electrophoresis. The results show that Fos is complexed with a basic 39-kDa protein (p39) in fibroblasts, and primarily with an acidic 40-kDa protein (p40) in PC12 cells. Whole cells lysates from both cell types contain p40, suggesting that the interaction of Fos and other cellular proteins is dependent on the differentiated state of the cell. In addition to p39 and p40, a heterogeneous population of polypeptides of approximately 48 kDa are present in Fos complexes isolated from non-denatured extracts of either cell type. These proteins may represent a minor class of Fos-binding proteins. Analysis of extracts prepared under denaturing conditions using antisera raised against a Fos peptide (amino acids 127-152) reveals a series of Fos-related antigens. These antigens are induced, some with a slower kinetics than Fos, in fibroblasts and PC12 cells. Thus, c-fos may represent a marker for a family of genes, some of which are antigenically related, that are part of an early cellular transcriptional response to diverse extracellular stimuli.

Animals↗
PubMed1992

Preproenkephalin mRNA in spinal dorsal horn neurons is induced by peripheral inflammation and is co-localized with Fos and Fos-related proteins.

Increased levels of preproenkephalin mRNA in spinal cord neurons induced by peripheral tissue inflammation were examined using in situ hybridization histochemistry. In addition, in situ hybridization histochemistry was combined with immunocytochemistry to determine whether increases in preproenkephalin mRNA were co-localized in spinal cord neurons with increases in immunoreactivity for Fos and Fos-related proteins coded by the immediate-early proto-oncogene, c-fos, and related genes. Dorsal horn laminae I-II, V-VI and VII showed a greater than 200% increase in preproenkephalin mRNA-labeled neurons on the inflamed side as compared to the contralateral control. Inflammation also induced Fos-like immunoreactivity in cell nuclei, mainly in the superficial laminae I-II and the neck of the dorsal horn (laminae V-VI). Few labeled nuclei were detected on the contralateral side. Inflammation resulted in double-labeling of neurons ipsilateral to the inflamed limb whereas they were almost completely absent on the contralateral side. Double-labeled neurons were most frequently found in laminae V-VI. Double-labeled laminae I-II neurons were concentrated in the medial two-thirds of the dorsal horn, the site that receives innervation from the inflamed limb. There were also many double-labeled neurons in laminae VII. Over 90%, 82% and 69% of all neurons expressing preproenkephalin mRNA co-localized Fos immunoreactivity in laminae V-VI, I-II, and VII, respectively. However, the number of neurons expressing increased Fos immunoreactivity was substantially greater than the subpopulation of double-labeled neurons. Our findings indicated that peripheral inflammation induces an increase in preproenkephalin mRNA levels in spinal cord neurons and that most neurons exhibiting preproenkephalin mRNA labeling also co-localized Fos and Fos-related immunoreactivity. These data are consistent with evidence supporting the role of Fos and Fos-related proteins in the regulation of transcription of the preproenkephalin gene in spinal neurons.

Animals↗