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PubMed2001

Effect of protein kinase C inhibitor (PKCI) on radiation sensitivity and c-fos transcription.

PURPOSE: The human genetic disorder ataxia-telangiectasia (AT) is a multisystem disease characterized by extreme radiosensitivity. Although ionizing radiation was known to induce c-fos transcription and cellular protein kinase C (PKC) induces the expression of this immediate response gene, little is known about how mutated AT (ATM) or PKC-mediated signal transduction pathway modulates the c-fos gene transcription and gene expression. Here we have studied the effect of PKC inhibitor (PKCI) on radiation sensitivity and c-fos transcription in normal and AT cells, and also studied whether PKCI effect on c-fos occurs in Ras-dependent pathway. METHODS AND MATERIALS: Normal (LM217) and AT (AT5BIVA) cells were transfected with PKCI expression plasmid and integration and overexpression of PKCI was evaluated by polymerase chain reaction and northern blotting, respectively. Cells were irradiated at a dose of 5 Gy/min with 137Cs irradiator and harvested 48 h after irradiation and investigated apoptosis with TUNEL method. The c-fos transcription activity was studied by performing compute assisted tomography (CAT) assay of reporter gene after transfection of c-fos CAT plasmid into LM and AT cells. Overexpression of Ras protein in transfected cells was shown by western blotting. RESULTS: Our results demonstrated for the first time a role of PKCI on the radiation sensitivity and c-fos transcription in LM and AT cells. PKCI increased radiation induced apoptosis in LM cells (5% to 20%) but reduced apoptosis slightly in AT cells. The basal c-fos transcription activity is 70 times lower in AT cells than in LM cells. This c-fos transcription activity was repressed by overexpression of PKCI in LM cells but not in AT cells. After induction of c-fos by Ras protein, overexpression of PKCI repressed c-fos transcription in LM cells but not in AT cells. CONCLUSIONS: Overexpression of PKCI increased radiation sensitivity and repressed c-fos transcription in LM cells but not in AT cells, and this is related with Ras. These results suggest that the effect of PKCI on c-fos transcription activity is related with Ras dependent signal transduction pathways and these mechanisms are different between normal fibroblasts, LM and ATM mutated, AT cells. The data obtained by this study provided evidence for novel transcriptional difference between LM and AT cells and this may be a reason for increased radiation sensitivity of AT cells.

Apoptosis↗
PubMed1993

Antisense rescue defines specialized and generalized functional domains for c-Fos protein.

Serum induces the expression of a number of proteins with similar transcriptional properties, including those encoded by the proto-oncogenes c-fos and c-jun. This study employs a novel antisense rescue method to determine whether antisense-resistant genes (constructed by deletion of antisense RNA target sequences) can replace c-fos expression during serum-induced DNA synthesis. Immunoprecipitation studies and nuclease protection assays demonstrated that anti-fos RNA inhibited endogenous c-fos expression but did not inhibit expression of transfected antisense-resistant mutant c-fos genes. The results of nuclear-labelling and cellular-proliferation studies indicated that C terminally truncated Fos mutants, including FBR v-fos, could not rescue endogenous Fos, although full-length and minimally truncated c-fos expression vectors could restore serum-induced DNA synthesis in cells expressing anti-fos RNA. Overexpression of c-Jun protein (Jun) could not restore serum-induced DNA synthesis to cells expressing inducible anti-fos RNA despite equivalent transactivation of an AP-1 target gene. Thus, the antisense rescue method defines a specialized function for c-Fos protein which is distinct from the function(s) of Jun and/or transforming FBR v-Fos proteins.

3T3 Cells↗
PubMed1995

Degradation of c-Fos by the 26S proteasome is accelerated by c-Jun and multiple protein kinases.

c-Fos is associated with c-Jun to increase the transcription of a number of target genes and is a nuclear proto-oncoprotein with a very short half-life. This instability of c-Fos may be important in regulation of the normal cell cycle. Here we report a mechanism for degradation of c-Fos. Coexpression of c-Fos and c-Jun in HeLa cells caused marked increase in the instability of c-Fos, whereas v-Fos, the retroviral counterpart of c-Fos, was stable irrespective of the coexpression of c-Jun. Interestingly, deletion of the C-terminal PEST region of c-Fos, which is altered in v-Fos by a frameshift mutation, greatly enhanced its stability, with loss of the effect of c-Jun on its stability. c-Fos synthesized in vitro was degraded by the 26S proteasome in a ubiquitin-dependent fashion. Simple association with c-Jun had no effect on the degradation of c-Fos, but the additions of three protein kinases, mitogen-activated protein kinase, casein kinase II, and CDC2 kinase, resulted in marked acceleration of its degradation by the proteasome-ubiquitin system, though only in the presence of c-Jun. In contrast, v-Fos and c-Fos with a truncated PEST motif were not degraded, suggesting that they escaped from down-regulation by breakdown. These findings indicate a new oncogenic pathway induced by acquisition of intracellular stability of a cell cycle modulatory factor.

Amino Acid Sequence↗
PubMed2001

Fos expression in rat celiac ganglion: an index of the activation of postganglionic sympathetic nerves.

To develop an index of the activation of abdominal sympathetic nerves, we used Fos immunostaining of the celiac ganglion (CG) taken from rats receiving nicotine, preganglionic nerve stimulation, or glucopenic agents. Subcutaneous nicotine injection moderately increased Fos expression in the principal ganglionic cells of the CG (17 +/- 4 Fos+ per mm(2), approximately 12% of all principal CG cells), whereas subcutaneous saline had no effect (0 +/- 0 Fos+ per mm(2); n = 7; P < 0.01). Greater Fos expression was obtained by applying nicotine topically to the CG (71 +/- 8 Fos+ per mm(2); 52% of all principal CG cells, n = 5; P < 0.01 vs. topical saline, n = 4) and by preganglionic nerve stimulation (126 +/- 9 Fos+ per mm(2); 94% of all principal CG cells, n = 11; P < 0.01 vs. nerve isolation, n = 7). Moderate Fos expression was also observed in the CG after intraperitoneal 2-deoxy-D-glucose (2DG) injection (21 +/- 2 Fos+ per mm(2); 16% of all principal CG cells, n = 5; P < 0.01 vs. saline ip) or insulin injection (16 +/- 2 Fos+ per mm(2); 12% of all principal CG cells, n = 6; P < 0.01 vs. saline ip). Furthermore, Fos expression induced by 2DG was dose and time dependent. These data demonstrate significant Fos expression in the CG in response to chemical, electrical, and reflexive stimulation. Thus Fos expression in the CG may be a useful index to describe various levels of activation of its postganglionic sympathetic neurons.

Animals↗
PubMed1995

Fos expression induced by changes in arterial pressure is localized in distinct, longitudinally organized columns of neurons in the rat midbrain periaqueductal gray.

The distribution of neurons expressing Fos within the periaqueductal gray (PAG) following pharmacologically induced high or low blood pressure was examined to determine (1) if PAG neurons are responsive to changes in arterial pressure (AP) and (2) the relationship of these cells to the functionally defined hypertensive and hypotensive columns in PAG. Changes in AP differentially induced robust Fos expression in neurons confined to discrete, longitudinally organized columns within PAG. Increased AP produced extensive Fos-like immunoreactivity within the lateral PAG, beginning at the level of the oculomotor nucleus. At the level of the dorsal raphe, Fos expression induced by increased AP shifted dorsally, into the dorsolateral division of PAG; this pattern of Fos labeling was maintained throughout the caudal one-third of PAG. Double-labeling for Fos and nicotinamide adenine dinucleotide phosphate diaphorase confirmed that Fos-positive cells induced by increased AP were located in the dorsolateral division of PAG at these caudal levels. Fos positive cells were codistributed, but not colocalized, with nicotinamide adenine dinucleotide phosphate diaphorase-positive cells. Decreased AP evoked a completely different pattern of Fos expression. Fos-positive cells were predominantly located within the ventrolateral PAG region, extending from the level of the trochlear nucleus through the level of the caudal dorsal raphe. Double-labeling studies for Fos and serotonin indicated that only 1-2 double-labeled cells per section were present. Saline infusion resulted in very few Fos-like immunoreactive cells, indicating that volume receptor activation does not account for Fos expression in PAG evoked by changes in AP. These results indicate that (1) substantial numbers of PAG neurons are excited by pharmacologically induced changes in AP and (2) excitatory barosensitive PAG neurons are anatomically segregated based on their responsiveness to a specific directional change in AP.

Animals↗
PubMed1989

The basic region of Fos mediates specific DNA binding.

The DNA-binding domains of the members of the Fos and Jun families of proteins consist of a basic region followed by a dimerizing segment with heptad repeats of leucine. Fos-Jun heterodimers and Jun alone, but not Fos alone, bind to the symmetrical sequences TGACTCA (AP-1 site) or TGACGTCA (cAMP response element or CRE). We set out to test the hypothesis that in the Fos-Jun heterodimer the basic region of Fos confers specific DNA-binding properties equivalent to the contribution of the basic region of Jun. Fos-Jun chimeric proteins were prepared consisting of the basic region of one protein joined to the leucine repeat of the other. Heterodimers with mixed Fos and Jun leucine repeat segments showed high affinity binding to the AP-1 site or CRE whether they contained two basic regions from Jun, two basic regions from Fos, or one from each source. Heterodimers with two Fos basic regions showed somewhat greater affinity for the CRE and AP-1 site than the heterodimer with two Jun basic regions. The DNA sequence specificity and the purine and phosphate DNA contact sites for each heterodimer were similar. We conclude that in the Fos-Jun heterodimer the basic region of Fos contributes specific DNA-binding properties equivalent to those of Jun. Our results support a model in which the Fos and Jun basic regions of the Fos-Jun heterodimer each interact with symmetrical DNA half sites.

Amino Acid Sequence↗
PubMed1993

Pulsatile and steady flow induces c-fos expression in human endothelial cells.

The effects of pulsatile and steady fluid flow on the mRNA levels of proto-oncogenes c-fos, c-jun, and c-myc in cultured human umbilical vein endothelial cells (HUVEC) were investigated. c-fos mRNA levels in stationary cultures were very low. A 1 Hz pulsatile flow with an average shear stress of 16 dynes/cm2 induced a dramatic increase of c-fos mRNA levels in HUVEC 0.5 h after the onset of flow, which declined rapidly to basal levels within 1 h. Steady flow with a similar shear stress also induced a transient increase of c-fos mRNA levels, but to a lesser extent. In addition, increased c-fos mRNA levels were observed when low shear (2-6 dynes/cm2) was replaced by high shear (16-33 dynes/cm2). Pulsatile and steady flow caused a slight increase of c-jun and c-myc mRNA levels. The role of pulsatility was also investigated in platelet-derived growth factor (PDGF) expression. Pulsatile flow induced a transient increase of PDGF A- and B-chain mRNA levels with peaks at 1.5-2 h. Pulsatile flow, which was more stimulatory in mediating c-fos expression, however, was less stimulatory than steady flow in mediating PDGF expression. By using various inhibitors, protein kinase C was found to be an important mediator in flow-induced c-fos expression, with the involvement of G proteins, phospholipase C, and intracellular calcium. Protein kinase C was previously shown as a possible major mediator in flow-induced PDGF expression which, at least partly, appeared to follow the induction mechanism of c-fos, suggesting a possible connection between c-fos and PDGF induction. However, the c-fos antisense treatment, which significantly inhibited c-fos transcription, failed to block the flow-induced PDGF expression, suggesting that flow-induced c-fos expression may not play an important role in the mechanism of flow-induced PDGF expression. The difference in the induction of c-fos and PDGF expression under pulsatile as compared to steady flow indicates that a complex, flow-mediated regulatory mechanism of gene expression exists in HUVEC. The increased expression of these proto-oncogenes mediated by flow may be important in regulating long-term cellular responses.

Base Sequence↗
PubMed1998

Transforming growth factor-beta1 and protein kinase C synergistically activate the c-fos serum response element in myocardial cells.

We previously reported that transforming growth factor-beta1 (TGF-beta1) potentiated alpha1-adrenergic and stretch-induced c-fos mRNA expression and norepinephrine (NE)-induced amino acid incorporation in rat cultured myocardial cells (MCs). In the present study, we attempted to explore the mode of TGF-beta1 action for c-fos gene expression in MCs. In the transient transfection assay, TGF-beta1 potentiated NE- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated c-fos promoter/enhancer, but not forskolin-activated c-fos promoter/enhancer. The c-fos serum response element (SRE) and the TPA response element (TRE) were responsible for TGF-beta1-induced potentiation of the NE or TPA action. Although TGF-beta1 activated not only the wild-type c-fos SRE, but also the mutated c-fos SRE, which contains an intact binding site for the serum response factor (SRF) but lacks the ternary complex factor (TCF) binding site, TPA activated the wild-type c-fos SRE but not the mutated c-fos SRE. TGF-beta1 did not potentiate the effects of TPA on the activation of mitogen-activated protein kinase (MAPK) and the phosphorylation of Elk-1 and SAP-1a, which belong to TCF at the c-fos SRE. These results indicate that TGF-betaf potentiates the c-fos SRE activated by PKC through the SRF binding site. TGF-beta1 is involved in the regulation of c-fos gene expression through the c-fos SRE and is subsequently involved in the regulation of the gene which has the TRE in the promoter/enhancer region.

Animals↗
PubMed1989

Adrenergic regulation of c-fos expression in cultured BC3H1 muscle cells.

Administration of adrenergic agonists induced c-fos mRNA in the salivary glands of the mouse and in the heart of the mouse, rat, and hamster (Barka et al., 1986, Mol. Cell Biol. 6, 2984-2989; 1987; Oncogene 1, 439-443). To further analyze transcriptional and post-transcriptional control of c-fos expression by adrenergic receptors and the putative role of fos in replication and differentiation pathways, we have examined c-fos expression in BC3H1 cells, a tumor-derived nonfusing muscle cell line. BC3H1 cells possess alpha 1- and beta 2-adrenergic receptors as well as receptors for histamine and acetylcholine. Furthermore, rapidly proliferating BC3H1 cells undergo differentiation toward muscle phenotype when exposed to low serum-containing culture media. Both alpha- and beta-adrenergic agonists and the tumor promoter 12-O-tetradecanoylphorbol-13-acetate caused a rapid, transient increase in the steady-state level of c-fos mRNA. This induction was essentially independent of whether the cells were in the proliferative, relatively quiescent, or differentiated state. Protein synthesis inhibitors cycloheximide and anisomycin also increased markedly the concentration of c-fos mRNA, and in the presence of anisomycin c-fos mRNA was superinduced by the alpha-adrenergic agonist norepinephrine. Run-on transcription assays indicated that the c-fos gene is expressed in both proliferating and differentiated cells, although the steady-state levels of c-fos mRNA were low, or even undetectable, in such cells. The adrenergic agonists and the tumor promoter stimulated the transcription of the c-fos gene in both proliferating and differentiated cells. This stimulation, however, was modest, two- to three-fold compared to controls, in contrast to the marked elevation of the level of c-fos mRNA they caused. Neither the proliferation nor the expression of muscle type creatine kinase activity was influenced by adrenergic agonists. It is suggested that activation of the c-fos gene is a consequence of adrenoreceptor stimulation in diverse cell types, and thus it is involved in pleiotropic cellular responses to adrenergic agonists. Catecholamines may be one of the physiologic regulators of the c-fos gene.

Animals↗
PubMed1991

Expression of the proto-oncogene c-fos following electrical kindling in the rat.

Kindling is a permanent form of brain change that results from repeated elicitation of epileptiform neural activity. c-fos has been proposed as the gene responsible for turning on molecular events that might underlie the long-term neural changes that occur during kindling. This study investigated the enhancement of c-fos levels following kindled seizures and the role of c-fos in the plastic changes underlying kindling. Male hooded rats were electrically kindled in the amygdala and the resulting c-fos and c-Ha-ras gene expression was quantified using Northern blot hybridization analysis. The results indicated that c-fos was constitutively expressed in forebrain and cerebellum, and that basal levels of c-fos were equivalent in naive and in fully kindled rats that have been seizure-free for 3 weeks. Following an amygdala-piriform kindled seizure there was a massive and transient increase in c-fos levels throughout forebrain and cerebellum. Although enhanced c-fos levels were correlated with afterdischarge (AD) duration in the kindled site, enhanced c-fos levels were also observed in the amygdala-piriform contralateral to the kindled site, and the enhancement did not depend on the occurrence of AD in the contralateral amygdala-piriform. Furthermore, electrical stimulations not resulting in AD as well as other forms of control stimulation also increased c-fos levels. We conclude that c-fos was expressed simply as a consequence of neural activity and not exclusively due to the specific neural activity or underlying plastic change required for kindling. This does not preclude a role for c-fos in the long-term response to external stimuli, but it does suggest that c-fos is not the crucial 'master switch' in turning on a molecular program that might underlie kindling.

Animals↗
PubMed1993

Oxytocin neuron activation and Fos expression: a quantitative immunocytochemical analysis of the effect of lactation, parturition, osmotic and cardiovascular stimulation.

As c-fos expression is generally thought to be linked to neuronal activation, we compared Fos immunoreactivity in identified oxytocinergic and vasopressinergic neurons of female rats under various conditions known to elicit particular patterns of electrophysiological and secretory activity in these neurons. In suckled lactating animals, Fos immunoreactivity was visible only in rare oxytocinergic and vasopressinergic neurons of the paraventricular and supraoptic nuclei, even after interruption of suckling for 18-72 h. On the other hand, many Fos-positive cells were visible in the nuclei of parturient rats; they involved about 25% of supraoptic oxytocinergic elements. Even more Fos-positive elements were visible in the nuclei of lactating rats that had also undergone 24 h water deprivation or haemorrhage. This involved about 75% vasopressinergic neurons and 25% oxytocinergic neurons of the supraoptic nucleus. Fos immunoreactivity was particularly conspicuous in oxytocin neurons of the anterior commissural nucleus after haemorrhage. After water deprivation or haemorrhage, Fos-positive oxytocinergic neurons in the supraoptic nucleus were significantly more numerous in virgin rats than in lactating rats. Our observations show that suckling, although a most potent stimulus for oxytocin neuron activation and oxytocin release, is inefficient in inducing Fos synthesis in magnocellular neurons, even after a period of interruption. On the other hand, parturition, water deprivation and haemorrhage were more potent stimuli for both neurosecretory systems. However, under each type of stimulation, only part of the neuronal populations within each nucleus were Fos-positive, suggesting that different stimulus-specific pathways are involved in these regulations. In so far as electrical activity is one possible mechanism for c-fos expression, comparison of the patterns of c-fos activation with the known electrophysiological behaviour of hypothalamic magnocellular neurons suggests that Fos synthesis in these neurons is linked to the number of action potentials generated over a period of time, more than to the pattern of electrical activity, whatever the physiological impact of this pattern. Furthermore, within a group of neurons, the heterogeneity of the response in terms of Fos synthesis may be correlated to the variability of the electrophysiological response within this group.

Animals↗
PubMed1994

Reserpine increases Fos activity in the rat basal ganglia via a quinpirole-sensitive mechanism.

Expression of the immediate early gene c-fos increases acutely following neuronal depolarization. c-fos and Fos protein have been widely used to investigate basal ganglia responses to changes in dopaminergic neurotransmission. Increased dopaminergic input to D1 receptors increases Fos synthesis in striatal neurons. The role of D2 receptors in regulating Fos activity has been more difficult to establish. Because dopamine is believed to excite striatal neurons via D1 receptors and inhibit them via D2 receptors, we hypothesized that acute dopamine depletion would increase Fos activity in basal ganglia circuits normally inhibited by dopaminergic input to D2 receptors. Rats were perfused after a single dose of the dopamine-depleting drug reserpine. The brains of rats perfused 3 h after reserpine displayed numerous Fos-like immunoreactive nuclei in the striatum, entopeduncular nucleus, nucleus accumbens shell, and ventral pallidum, and sparse Fos-like immunoreactive nuclei in the globus pallidus and nucleus accumbens core. Few or no Fos-like immunoreactive nuclei were seen following perfusion 30 min, 60 min, and 24 h after reserpine. In the 3-h paradigm, pretreatment with the selective D1 antagonist SCH 23390 did not change the pattern of Fos-like immunoreactivity; pretreatment with the selective D2 agonist quinpirole completely blocked increased Fos synthesis. Acute dopamine depletion, therefore, increases Fos activity in the basal ganglia by disinhibiting D2 circuits. These results support the parallel pathway model of basal ganglia function, and show that Fos can be used to investigate the role of D2 receptors in striatal function. The findings suggest anatomic correlates for the clinical effects of acute dopamine depletion in drug therapy and advanced Parkinson's disease in humans.

Animals↗
PubMed1994

Expression of Fos-like protein in brain following sustained hypertension and hypotension in conscious rabbits.

The purpose of this study was to examine comprehensively and quantitatively the effects of sustained hypertension and hypotension on neuronal expression of Fos, the protein product of the proto-oncogene c-fos, in the brain of conscious rabbits. Hypertension or hypotension was produced by continuous intravenous infusion of phenylephrine or nitroprusside, at a rate sufficient to increase or decrease, respectively, arterial pressure by 20-30 mmHg, maintained for a period of 60 min. In comparison with a sham control group of rabbits that were infused with the vehicle solution alone, hypertension induced a significant increase in Fos immunoreactivity in the area postrema, the nucleus tractus solitarii, the caudal and intermediate ventrolateral medulla, the lateral parabrachial nucleus and the central nucleus of the amygdala. Double-labelling for tyrosine hydroxylase and Fos immunoreactivity showed that few (approximately 5%) of the Fos-positive neurons in the caudal and intermediate ventrolateral medulla in this group of animals were also positive for tyrosine hydroxylase. Hypotension also produced a significant increase in Fos immunoreactivity in the above regions, as well as in the rostral ventrolateral medulla, the A5 area, the locus coeruleus and subcoeruleus, the paraventricular nucleus, the supraoptic nucleus, the arcuate nucleus and the medial preoptic area. Approximately 65% of neurons in the rostral, intermediate and caudal ventrolateral medulla that expressed Fos following hypotension were also positive for tyrosine hydroxylase. Similarly, in the pons, approximately 75% of Fos-positive cells in the locus coeruleus, subcoeruleus and A5 area were positive for tyrosine hydroxylase. In the hypothalamus, 92% of Fos-positive neurons in the supraoptic nucleus, and 37% of Fos-positive neurons in the paraventricular nucleus, were immunoreactive for vasopressin. Our results demonstrate that hypertension and hypotension induce reproducible and specific patterns of Fos expression in the brainstem and forebrain. The distribution patterns and chemical characteristics of Fos-positive neurons following sustained hypertension or hypotension are significantly different. In particular, hypotension, but not hypertension, caused Fos expression in many tyrosine hydroxylase-positive cells within all pontomedullary catecholamine cell groups.

Animals↗
PubMed1996

c-fos Expression in the rat brain after unilateral labyrinthectomy and its relation to the uncompensated and compensated stages.

The expression of the immediate early gene c-fos has been studied in the entire brain of rats 3, 6 and 24 h after surgical unilateral labyrinthectomy. We combined in situ hybridization for c-fos messenger RNA with immunocytochemistry for Fos protein to document very early changes in c-fos expression and to identify with cellular resolution neuronal populations activated by unilateral labyrinthectomy. Three hours after unilateral labyrinthectomy a bilateral increase in both c-fos messenger RNA and protein levels was seen in the superior, medial and spinal vestibular nuclei, nucleus Y, and prepositus hypoglossal nucleus. These changes were asymmetric in the medial vestibular nucleus, being most prominent in the dorsal part of the contralateral nucleus (where second order vestibular neurons are located) and in the ventral part of the ipsilateral nucleus (where commissural neurons acting on the medial vestibular nucleus of the intact side are located). An increase in c-fos messenger RNA expression was seen bilaterally, but with an ipsilateral predominance, in the vermal and paravermal areas of the cerebellar cortex, flocculus and paraflocculus, as well as in the precerebellar lateral and paramedian reticular nuclei. c-fos messenger RNA and protein levels increased in a few regions of the contralateral inferior olive. A predominantly ipsilateral increase in c-fos expression also occurred in the caudate-putamen. A bilateral but not exactly symmetric increase in both c-fos messenger RNA and protein levels was present in several nuclei of the dorsal pontine tegmentum (parabrachial nucleus, locus coeruleus and laterodorsal tegmental nucleus), mesencephalic periaqueductal gray, and several hypothalamic, thalamic and cerebrocortical regions. No change was seen in the cerebellar nuclei, lateral vestibular nucleus and red nucleus. The increased expression of c-fos observed 3 h after unilateral labyrinthectomy, in conjunction with the sudden occurrence of postural and motor deficits, usually declined 6-24 h after the lesion, i.e. during the development of vestibular compensation. In the dorsal part of the medial vestibular nucleus, however, the pattern of c-fos expression observed 3 h after unilateral labyrinthectomy was reversed 6-24 h after the lesion: both c-fos messenger RNA and protein levels increased on the ipsilateral side, but greatly decreased on the contralateral side. In conclusion, asymmetric changes in c-fos expression occurred within 3 h after unilateral labyrinthectomy, but gradually declined or reversed 6 and 24 h after the lesion, thus being temporally related to the appearance and development of vestibular compensation.

Animals↗
PubMed1996

Differential c-fos expression in the nucleus of the solitary tract and spinal cord following noxious gastric distention in the rat.

c-Fos has been used as a marker for activity in the spinal cord following noxious somatic or visceral stimulation. Although the viscera receive dual afferent innervation, distention of hollow organs (i.e. esophagus, stomach, descending colon and rectum) induces significantly more c-Fos in second order neurons in the nucleus of the solitary tract and lumbosacral spinal cord, which receive parasympathetic afferent input (vagus, pelvic nerves), than the thoracolumbar spinal cord, which receives sympathetic afferent input (splanchnic nerves). The purpose of this study was to determine the contribution of sympathetic and parasympathetic afferent input to c-Fos expression in the nucleus of the solitary tract and spinal cord, and the influence of supraspinal pathways on Fos induction in the thoracolumbar spinal cord. Noxious gastric distention to 80 mmHg (gastric distension/80) was produced by repetitive inflation of a chronically implanted gastric balloon. Gastric distension/80 induced c-Fos throughout the nucleus of the solitary tract, with the densest labeling observed within 300 microns of the rostral pole of the area postrema. This area was analysed quantitatively following several manipulations. Gastric distension/80 induced a mean of 724 c-Fos-immunoreactive nuclei per section. Following subdiaphragmatic vagotomy plus distention (vagotomy/80), the induction of c-Fos-immunoreactive nuclei was reduced to 293 per section, while spinal transection at T2 plus distention (spinal transection/80) induced a mean of 581 nuclei per nucleus of the solitary tract section. Gastric distension/80 and vagotomy/80 induced minimal c-Fos in the T8-T10 spinal cord (50 nuclei/section), but spinal transection/80 induced 200 nuclei per section. Repetitive bolus injections of norepinephrine produced transient pressor responses mimicking the pressor response produced by gastric distension/80. This manipulation induced minimal c-Fos in the nucleus of the solitary tract and none in the spinal cord. It is concluded that noxious visceral input via parasympathetic vagal afferents, and to a lesser extent sympathetic afferents and the spinosolitary tract, contribute to gastric distention-induced c-Fos in the nucleus of the solitary tract. The induction of c-Fos in the nucleus of the solitary tract is significantly greater than in the viscerotopic segments of the spinal cord, which is partially under tonic descending inhibition, but is not subject to modulation by vagal gastric afferents. Distention pressures produced by noxious gastric distention are much greater than those produced during feeding, suggesting that c-Fos induction in the nucleus of the solitary tract to noxious distention is not associated with physiological mechanisms of feeding and satiety. The large vagal nerve-mediated induction of c-Fos in the nucleus of the solitary tract following gastric distension suggests that parasympathetic afferents contribute to the processing of noxious visceral stimuli, perhaps by contributing to the affective-emotional component of visceral pain.

Afferent Pathways↗
PubMed2005

c-fos overexpression in splenic B cells augments development of marginal zone B cells.

Marginal zone (MZ)-B cells participate in very early immune responses and play a pivotal role in the first-line of defense against blood-borne Ags including bacterial LPS. Since splenic B cells from c-fos transgenic (H2-c-fos) mice are hyper-sensitive to LPS stimulation, we examined LPS-sensitivity of MZ-B cells in the spleen of H2-c-fos mice. Here, we show that proliferation of MZ-B cells from H2-c-fos mice stimulated with LPS was larger than that from control mice. Proliferation and IgM production of the H2-c-fos MZ-B cells were also larger than those of splenic follicular (FO)-B cells from the H2-c-fos mice, suggesting that c-fos overexpression augments LPS-sensitivity of MZ-B cells more than that of FO-B cells. Furthermore, the number of MZ-B cells but not that of FO-B cells in the spleen of H2-c-fos mice was two- to three-fold larger than that in control littermates. The number of transitional type II (T2)-B cells in H2-c-fos mice was also larger than that of control littermates. However, the number of transitional type I (T1)-B cells in the spleen of H2-c-fos mice was not larger than that of control mice. Moreover, this c-fos effect on differentiation of MZ-B cells was intrinsic in B cells by the competitive repopulation assay with hematopoietic stem cells of H2-c-fos and control mice. These results suggest that c-fos overexpression in B cells augments differentiation and accumulation of MZ-B cells.

Animals↗
PubMed2001

Effects of prolonged wakefulness on c-fos and AP1 activity in young and old rats.

Recent studies have demonstrated that the immediate-early gene c-fos is induced in neuronal populations responsible for specific sleep-wake states. The induction of this gene may be functionally relevant to sleep homeostasis since without the gene mice (c-fos null) take longer to fall asleep and have a selective reduction in slow-wave sleep. This suggests that a build-up of c-fos during wakefulness increases the drive to sleep and lack of c-fos is associated with reduced sleep. Sleep also has an effect on c-Fos serving to eliminate the protein rapidly. Waxing and waning of transcription factors such as c-Fos may influence slow, oscillating events such as sleep and wakefulness. To further examine what role c-Fos may play in regulating sleep, the present study examined the effects of prolonged wakefulness on c-Fos and AP-1 activity in young (3.5 months old) and old (21.5 months old) Sprague--Dawley rats. Previously we found that old rats slept less even after prolonged wakefulness, and other investigators have found that aging is also associated with a decline in c-Fos. In the present study, we reasoned that prolonged wakefulness would also fail to increase c-Fos in old versus young rats. The baseline levels of c-Fos and AP-1 activity were not different between young and old rats. However, in response to 6 or 12 h of prolonged wakefulness, old rats demonstrated significantly less c-Fos and AP-1 activity compared to young rats. These findings suggest that in old rats the mechanism responsible for c-Fos induction in response to wakefulness is deficient. Such a decline at the molecular level could contribute to the decline in sleep that typically occurs with age.

Aging↗
PubMed2002

Colonic inflammation induces fos expression in the thoracolumbar spinal cord increasing activity in the spinoparabrachial pathway.

The descending colon and rectum are innervated by primary afferent fibers projecting to the lumbosacral and thoracolumbar spinal cord segments. Previous work from this laboratory has suggested that afferent input and sensory processing in the lumbosacral spinal cord is necessary and sufficient to mediate reflex responses to transient colorectal stimulation while processing in both the lumbosacral and thoracolumbar spinal cord segments contribute to visceral hyperalgesia. In the rat, repetitive noxious colorectal distention (CRD) induces >200 Fos labeled cells per section in the lumbosacral segments, but few in the thoracolumbar segments, further suggesting that transient colonic nociceptive input is transduced primarily in the lumbosacral spinal cord. The laminar distribution of this CRD-induced Fos suggests some of these neurons project to the parabrachial nucleus (PBn), an important relay for visceroceptive input from the spinal cord to higher order centers for nociceptive processing. In this study, two hypotheses were tested: first, inflammation of the colon prior to CRD would induce Fos expression in neurons in the thoracolumbar spinal cord segments and increase the number of neurons in the lumbosacral spinal cord segments that express Fos in response to noxious CRD; and second, the inflammation-induced increase in Fos expression in the spinal cord would be partially manifest as an increase in the number of spinoparabrachial projection neurons that respond to CRD. The retrograde tracer Fluorogold (FG) was injected unilaterally into the PBn of male Sprague-Dawley rats. Ten to 14 days later the rat's colon was either distended or inflamed and distended. Sections from the T13-L2 and L6-S2 spinal cord segments were double labeled using antibodies directed against FG and Fos protein. The results show that: (1) colonic inflammation plus distention induced Fos expression in the thoracolumbar spinal cord and increased Fos expression in the lumbosacral spinal cord compared to distention alone. In the lumbosacral cord, the increase in Fos expression was localized primarily to the superficial dorsal horn (SDH). In the thoracolumbar spinal segments, Fos was induced primarily in the SDH and the area around the central canal. (2) Injection of FG into the PBn produced dense retrograde labeling in the SDH, the lateral deeper gray matter and the area around the central canal at the lumbosacral and thoracolumbar levels. (3) In the lumbosacral spinal cord, 30-40% of the FG labeled cells double labeled for Fos. Colonic inflammation plus CRD did not significantly increase the percentage of spinoparabrachial neurons that were labeled for Fos compared to distention alone. (4) In the thoracolumbar spinal cord less than 10% of the FG labeled neurons were double labeled for Fos following CRD, but 25% of the FG labeled neurons in the SDH were double labeled following colonic inflammation. These data support the hypothesis that colonic inflammation activates viscerosensory processing in the thoracolumbar spinal cord and further suggests that this information is relayed to the PBn. The increase in information reaching the PBn over these parallel pathways may contribute to the affective-motivational component of the pain experience.

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