l-Dopa stimulates c-fos expression in dopamine denervated striatum by combined activation of D-1 and D-2 receptors

Administration of l-dopa to unilaterally 6-hydroxydopamine-lesioned rats, activates the early gene c-fos in the lesioned caudate-putamen. D-1 receptor blockade by SCH 23390, preventedl-dopa-induced Fos-like immunoreactivity in the whole caudate-putamen, while D-2 receptor blockade by raclopride reduced Fos-like immunoreactivity only in the dorso-lateral portion. The results suggest thatl-dopa induces c-fos primarily through an activation of D-1 receptors, while D-2 receptor stimulation plays a facilitatory influence on D-1 mediated c-fos expression.     

The relationship between c-myc protein expression,the bromodeoxyuridine labeling index and the biological behavior of pituitary adenomas

Summary To clarify the relationship between the percentage of c-myc protein-labeled cells, the bromodeo-xyuridine (BrdUrd) labeling index (LI) and clinical malignancy in pituitary adenomas, we studied 31 cases of pituitary adenomas. Tumor invasiveness, recurrence, tumor size and the length of illness were evaluated from operative findings, magnetic resonance imaging findings, and the clinical course. Each pituitary adenoma was scored to represent the degree of clinical malignancy. An hour before excision of the tumor, we administered BrdUrd intravenously. Surgical materials were fixed in 70% alcohol and embedded in paraffin. Both hematoxylin and eosin staining and immunohistochemical staining were performed using a monoclonal antibody for both anti-BrdUrd and anti-c-myc protein. Among pituitary adenomas, there was a significantly low percentage of c-myc protein-labeled cells in cases with acromegaly. The percentage of c-myc protein-labeled cells in the pituitary adenomas tended to increase with increase with the total scores of clinical malignancy. The BrdUrd LI was lower than 1% in almost all cases of pituitary adenomas, and it showed no correlation with their clinical malignancy. In conclusion, determination of the percentage of c-myc protein-labeled cells in pituitary adenomas proved to be useful for evaluating their clinical malignancy.     

Immunohistochemical expression of apoptosis regulating proteins and sex hormone receptors in meningiomas

Meningiomas are well known to be responsive to estrogen/progesterone stimulation, and their expression of estrogen/progesterone receptor (ER/PR) has been documented. On the other hand, there are several reports studying expression of apoptosis‐regulating proteins (ARPs) and its significance in meningiomas. However, very limited published information exists on the exact relation among sex hormone receptor status, apoptosis, proliferation index (PI), and histological grade in meningiomas. A total of 57 cases of non‐malignant meningiomas were selected, and histologically reviewed and graded (WHO grades 1, 2). All these cases were immunostained for ER, PR, Ki‐67, and ARPs including bax, bcl‐2, and bcl‐xL. Sections were graded semiquantitatively for intensity and extent of immunostaining. PI was expressed as a percentage of Ki‐67 positive tumor cells. Expression of bax, bcl‐2, bcl‐xL, ER, and PR was seen in 100, 35.1, 24.6, 10.4, and 87.2% of cases, respectively. Bax was expressed diffusely and strongly, while Bcl‐2 tended to be expressed weakly and focally. Bcl‐xL appeared to be expressed relatively strongly and diffusely in a small subset. There was significantly higher PI as well as expression of PR in grade 1 group than in grade 2 group. A weak negative correlation was observed between Bcl‐2 and PR (r =?0.472, P < 0.0014). Given high‐level expression of pro‐apoptotic bax, which seems to be constitutionally expressed, in contrast to low‐level expression of antiapoptotic bcl‐2 and bcl‐xL, other antiapoptotic proteins may involve the proliferation of meningiomas. A significant negative relation exists between PR and Bcl‐2 in meningiomas, which might have some biological and clinical significance.     

Distinct mechanisms for expression of Fos-like immunoreactivity and synaptic potentiation in telencephalic hyperstriatum of the quail chick

In the intermediate and medial hyperstriatum ventrale (IMHV), a telencephalic region essentially involved in the initial processes of early learning tasks in poultry chicks, induction of an immediate early gene c-fos correlates significantly with the degree of learning (K.V. Anokhin, R. Mileusnic, I.Y. Shamakina, S.P.R. Rose, Effects of early experience on c-fos gene expression in the chick forebrain, Brain Res. 544 (1991) 101–107; B.J. McCabe, G. Horn, Learning-related changes in Fos-like immunoreactivity in the chick forebrain after imprinting, Proc. Natl. Acad. Sci. USA 91 (1994) 11417–11421). In slices of IMHV in vitro, on the other hand, tetanic stimulation at a low frequency induces a potentiation of synaptic responses (P.M. Bradley, B.D. Burns, A.C. Webb, Potentiation of synaptic responses in slices from the chick forebrain, Proc. R. Soc. Lond. B. 243 (1991) 19–24; T. Matsushima, K. Aoki, Potentiation and depotentiation of DNQX-sensitive fast excitatory synaptic transmission in telencephalon of the quail chick, Neurosci. Lett. 185 (1995) 179–182). In this study, we have examined a possible causal link between these two forms of activity-dependent processes, c-fos expression and synaptic potentiation. C-fos was visualized immunohistochemically using antibody raised against the Fos-protein, and potentiation was evaluated on the basis of field potential responses to local electrical stimulation. Tetanic stimulation (5 Hz×300 pulses) was required for potentiation, but not for c-fos expression. Conversely, a negative correlation appeared between them, and slices with relatively high density of Fos-like immunoreactive cells around the stimulation site failed to show potentiation. Furthermore, drugs similarly effective in blocking potentiation (such as AP5 (NMDA receptor antagonist) and bicuculline (GABA_A receptor antagonist)) had different effects on the c-fos induction. While AP5 had minor, if any, effects on c-fos expression, bicuculline enhanced it selectively around the site of stimulation. Our results suggest that these two processes are basically distinct, and could represent different aspects in the formation of memory traces in IMHV.     

Gonadal steroid receptors in meningiomas

Summary Oestrogen receptor (ER) analysis was performed in 70 meningiomas with an enzyme immunoassay, using monoclonal antibodies against human oestrogen receptor protein (oestrophilin) and with a sensitive radioligand binding assay, using ¹²⁵I-oestradiol as radioligand. Low levels of ER immunoreactivity were found in tumours from 51% of patients, whereas ER binding activity was demonstrated in 40% of the meningiomas examined. In 8 (11%) tissue samples multiple binding sites for oestradiol were observed. The immunoreactive binding sites corresponded to the classical, high-affinity ER. In ligand binding studies, however, measurement of classical ER was considerably influenced by a second low-affinity, high-capacity oestrogen binding component even at low ligand concentrations. ³H-methylpromegestone and ³H-methyltrienolone, a synthetic gestagen and androgen, were used for concurrent determination of the progesterone receptor (PR) and androgen receptor (AR) binding activity. High concentrations of PR were detected in 53 (76%), whereas moderate levels of AR binding sites were demonstrated in 33 (47%) tumours. A positive correlation between ER immunoreactivity and AR binding activity is indicative for an oestrogen regulation of AR via the ER system. The presence of gonadal steroid receptors in a large proportion of meningiomas and the tendency for a dependence of receptor concentrations on the histological subtype could have implications for tumour therapy.     

Effect of locus coeruleus lesion on c-fos expression in the cerebral cortex caused by yohimbine injection or stress

The injection of the α-2 adrenoceptor antagonist, yohimbine, has been shown to increase c-fos immunoreactivity in the rat cerebral cortex. To determine the extent to which this response is mediated by the central noradrenergic system, the present studies examined it in rats previously given unilateral 6-OHDA lesions of the locus coeruleus. The lesions were found to produce a significant attenuation of the response. A similar effect on the c-fos immunoreactive response to restraint stress was found. It is concluded that the noradrenergic system plays a necessary role in the above c-fos responses in the cortex to yohimbine and to stress. The c-fos protein therefore appears to be involved in the effects of noradrenergic neurotransmission in the CNS.     

Immunohistochemical expression of aromatase and estrogen,androgen and progesterone receptors in normal and neoplastic human meningeal cells

Evidence suggests that sex hormones may play a role in the tumorigenesis of meningiomas, and studies have demonstrated the expression of hormone receptors in these tumors. Aromatase expression has been detected in several normal tissues, including neurons in the CNS, and tumor tissues. We aim to assess the expression of aromatase (ARO) and of progesterone receptor (PR), estrogen receptor (ER) and androgen receptor (AR) in both normal and neoplastic meningeal cells. A cross‐sectional study was conducted with 126 patients diagnosed with meningioma (97 women and 29 men; mean age, 53.6 years) submitted to neurosurgery at Hospital São José, Complexo Hospitalar Santa Casa de Porto Alegre, southern Brazil. Control sections of normal meningeal cells, 19 patients, were obtained by evaluating the arachnoid tissue present in the arachnoid cyst resected material. Immunohistochemistry was applied to assess ARO, PR, ER and AR. Aromatase expression was detected in 100% of the control patients and in 0% of the patients with meningioma. ER was present in 24.6% of the meningiomas and in 0% of the controls, AR in 18.3% of the meningiomas and in 0% of the controls, and PR in 60.3% of the meningiomas and in 47.4% of the controls. A positive association was observed between the presence of AR and ER (OR 3.7; P = 0.01) in meningiomas. There were no significant differences in the presence of hormone receptors between meningioma histological subtypes. PR expression in women with meningioma was significantly higher than that found in men (OR 2.3; P = 0.08). Behavior pattern differences observed between aromatase expression, present in normal tissues and absent in meningiomas, and estrogen and androgen hormone receptors, absent in normal tissues and present in meningiomas, suggest that there is heterogeneity in modulation by sex steroids in the development of these tumors.     

Oxytocin neurons in the rat hypothalamus exhibit c-fos immunoreactivity upon osmotic stress

In order to evaluate the responses to osmotic stress of oxytocinergic neurons in vivo, we have studied oxytocin (OXY) and c-fos protein expression in the brain by means of double-immunostaining. C-fos immunoreactivity was detected in a subset of OXY neurons, as well as in other neurons non-immunoreactive for OXY, as early as 90 min after intraperitoneal injection of a hypertonic saline solution. C-fos expression was found in approx. 70% of OXY-immunoreactive neurons in the supraoptic (SON), lateral subcommisural (LSN) and paraventricular (PVN) nuclei, and not in OXY neurons in other hypothalamic areas. The expression of c-fos may be used as a means to map the circuitry by which osmotic stimulation activates OXY-containing neurons, and thus provide further insights into the functions with which OXY may be associated.     

Gonadotropin-releasing hormone (GnRH) and its receptor in human meningiomas

Objective

Meningiomas are the most common neoplasms of the central nervous system and are more frequent in women than in men. Many studies have been conducted to determine whether the progesterone receptor (PR) and estrogen receptor (ER) are present or absent in meningiomas. No previous studies, however, have investigated the status (presence or absence) of gonadotropin-releasing hormone (GnRH) and its receptor (GnRH-R), two major factors related to PR and ER, in meningiomas. This study aims to determine the status of GnRH and GnRH-R and to elucidate the correlations of GnRH and GnRH-R with PR, ER, and clinical features in meningiomas.

Methods

Eighty-two specimens of human meningiomas were obtained for immunohistochemical analysis with anti-GnRH, anti-GnRH-R, anti-PR, anti-ER, and anti-Ki-67 (MIB-1) antibodies, and for RT-PCR analysis of the mRNA expressions of GnRH and GnRH-R. Correlations of GnRH and GnRH-R with PR, ER, Ki-67, and clinical features such as age, sex, tumor grade, and tumor histology were assessed.

Results

Seventy-eight (95.1%) of the 82 meningiomas reacted positively in the cytoplasm for the GnRH-R. Forty-nine (59.8%) of the 82 cases reacted positively in the cytoplasm for the GnRH. The positive immunoreactivity for GnRH-R and GnRH was confirmed by the RT-PCR analyses of mRNA. Forty-seven (96%) of the 49 cases with positive immunoreactivity for GnRH-R also had positive immunoreactivity for GnRH. PR expression was higher in the tumors positive for GnRH-R (p = 0.002), and a significantly higher proportion of tumors from male patients exhibited positive immunoreactivity for GnRH (p = 0.02). No significant correlations were found between the status of GnRH-R or GnRH with other clinicopathological features.

Conclusion

Over half of meningiomas may be regulated by GnRH–GnRH-R expression in an autocrine fashion. This unique expression profile of GnRH and GnRH-R may open the way to the development of GnRH analogs as a treatment tool in the future.     

Clinicopathological and molecular characteristics of pediatric meningiomas

Molecular and clinical characteristics of pediatric meningiomas are poorly defined. Therefore, we analyzed clinical, morphological and molecular profiles of pediatric meningiomas. Forty pediatric meningiomas from January 2002 to June 2015 were studied. 1p36, 14q32 and 22q‐deletion were assessed by fluorescent in situ hybridization and mutations of most relevant exons of AKT, SMO, KLF4, TRAF and pTERT using sequencing. Expression of GAB1, stathmin, progesterone receptor (PR), p53 along with MIB‐1 LI was examined using immunohistochemistry. There were 36 sporadic and four NF2 associated meningiomas. Among sporadic meningiomas, the majority (72.2%) of cases harbored 22q‐deletion. Difference in frequency of combined 1p/14q deletion in Grade‐I versus Grade‐II/III tumors was not significant (13.7% vs 28.5%, P = 0.57). PR immunoreactivity was seen in 65.5% of Grade‐I and 14.2% of Grade‐II/III tumors (P = 0.03). The majority (97.2%) of meningiomas were immunonegative for p53. Stathmin and GAB co‐expression was observed in 58.3% of cases. Notably, AKT, SMO, KLF4, TRAF7 (exon 17) and pTERT mutations were seen in none of the cases analyzed. 1p/14q codeletion was frequent in skull base as compared to non‐skull base meningiomas (23% vs 11.1%, P = 0.37). All NF2 meningiomas harbored 22q‐deletion and showed GAB and stathmin co‐expression while none showed 1p/14q loss. Pediatric meningiomas share certain phenotypic and cytogenetic characteristics with adult counterparts, but GAB and stathmin co‐expression in the majority of cases and non‐significant difference in frequency of 1p/14q co‐deletion between low‐ and high‐grade meningiomas indicate an inherently aggressive nature. Characteristic AKT/SMO, KLF4/TRAF7 and pTERT genetic alterations seen in adults are distinctly absent in pediatric meningiomas.     

Activation of anterior lobe corticotrophs by electroacupuncture or noxious stimulation in the anaesthetized rat, as shown by colocalization of fos protein with ACTH and β-endorphin and increased hormone release

A marked expression of the c-fos proto-oncogene has been recently reported in cells of the anterior lobe of the pituitary gland in rats subject to electroacupuncture or noxious thermal stimulation under pentobarbital anaesthesia. The present study was undertaken to identify the activated pituitary cells. Following both kinds of stimulation, most Fos-immunoreactive anterior lobe cells showed colocalization with adrenocorticotropic hormone or β-endorphin immunoreactivity. No c-fos expression occurred in pituitary cells immunoreactive for growth hormone, prolactin, luteinizing hormone, or thyrotrophin-stimulating hormone. A marked rise of adrenocorticotropic hormone and β-endorphin concentrations occurred in plasma. In the hypothalamus, c-fos expression was increased in the mediobasal nuclei—namely, the arcuate nucleus—and in the paraventricular nucleus, but more in the former. It is suggested that somatosensory noxious input, or the partly noxious input evoked by electroacupuncture, activate the hypothalamo-pituitary-adrenocortical axis as in common forms of stress, but with a specific activation of the mediobasal hypothalamic nuclei and no stimulation of intermediate lobe cells. Opiate release from the pituitary gland may contribute to acupuncture analgesia or the intrinsic antinociceptive reactions triggered by noxious stimulation.     

Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain

The present study was directed at evaluating the possible involvement of protein synthesis in excitotoxin-induced neuronal damage and prolonged expression of the proto-oncogene, c-fos. Kainic acid-induced seizure activity elicited varying degrees of neuronal damage and cell loss in selectively vulnerable regions of the adult rat limbic system. Pretreatment with cycloheximide, a protein synthesis inhibitor, did not alter behavioral seizure characteristics, but markedly attenuated damage to susceptible neuronal populations. A prolonged increase in c-fos mRNA was observed byin situ hybridization up to 16 h after the onset of seizures in regions exhibiting neuronal death. Pretreatment with cycloheximide did not affect the transient induction of c-fos observed in numerous structures, but significantly reduced the prolonged expression of c-fos mRNA in kainatevulnerable regions. Despite producing massive seizure activity, systemic kainic acid administration during the early postnatal period did not induce any neuronal death, and did not result in prolonged c-fos expression in any brain structures. The developmental onset of selective neuronal vulnerability coincided with that of prolonged c-fos expression in susceptible neuronal populations. In adult rats, seizure activity induced by pentylenetetrazole did not produce neuronal damage nor did it produce prolonged c-fos expression. These results not only demonstrate that kainate-induced neurotoxicity and the prolonged expression of c-fos are both prevented by cycloheximide, but also strengthen the idea that prolonged c-fos expression is a marker of neuronal death.     

Adenosine A2A receptor agonists increase Fos-like immunoreactivity in mesolimbic areas

Expression of the early-gene c-fos is an useful method for studying potential sites of action of drugs active in the CNS. Stimulation of adenosine A_2A receptors by CGS 21680 (5 mg/kg) induced an increase in Fos-like immunoreactivity in the rat nucleus accumbens shell, while in the rostral pole and core CGS 21680 induced Fos-like immunoreactivity only after a high dose. CGS 21680 (5 mg/kg) stimulated c-fos expression also in the lateral septal nucleus and dorso-medial striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A_2A agonist HENECA (5 mg/kg) which displays higher selectivity for A_2A receptors than CGS 21680. Administration of the selective A_2A antagonist SCH 58261 counteracted CGS 21680-induced Fos-like immunoreactivity. Lesions of the dopaminergic mesostriatal projection by 6-hydroxydopamine and stimulation of dopamine D₂/D₃ receptors by quinpirole, prevented CGS 21680-induced Fos-like immunoreactivity in the nucleus accumbens shell. The present results show that stimulation of A_2A receptors induces a profile of c-fos expression similar to that of atypical neuroleptics. A_2A receptor stimulation has been reported to have dopamine antagonistic actions, it is therefore suggested that A_2A agonists might have antipsychotic activity without producing extrapyramidal side effects.     

Platelet–derived growth factor (PDGF) and receptor (PDGFR) expression in human meningiomas: correlations with clinicopathological features and cytogenetic analysis

PDGFs and their receptors expression were examined in a series of 46 meningiomas by using specific monoclonal antibodies. The immunostaining was quantified by an image analyser and the results correlated with clinical and morphological data (histological type and grade). In addition, since the PDGFB chain is encoded by the c–sis proto–oncogene localized on chromosome 22 and because monosomy 22 has been frequently reported in meningiomas, PDGFs and PDGFRs expression have been correlated with cytogenetic analysis performed in 29 cases. The results demonstrate PDGF A and PDGFB expression in most meningioma specimens and co–expression of these growth factors in numerous cells. PDGF A and B immunoreactivity was related to histo logical grade. PDGFR βexpression was strong in almost all meningiomas whereas PDGFR α was low. PDGFR α expression was related to tumour location and grade and PDGFR β to histological subtype only. The cytogenetic analysis was not related to PDGFB chain expression. Taken together these data further confirm PDGF and PDGFR expression in human meningioma; PDGF may exist as an heterodimer (AB) as well as its receptor. The lack of correlation between cytogenetic analysis and PDGF values, the low level of PDGFB in recurrent meningiomas suggests that it is unlikely that the c–sis proto–oncogene plays an important role in the genesis of meningiomas.     

Zif268 and Fos-like immunoreactivity in tetanus toxin-induced epilepsy: reciprocal changes in the epileptic focus and the surround

Altered gene expression for a number of molecules has been suggested as one of the underlying mechanisms of epileptogenesis. Changes in expression of the immediate early genes, zif268 and c-fos, were investigated in chronic focal epilepsy induced by tetanus toxin (TT, 20–35 ng) injected in the rat motor cortex. Most rats injected with TT and perfused on postoperative day 5, 7 or 14 had recurrent focal seizures after a latent period of 4–13 days, and showed enhanced Zif268 immunoreactivity in a cluster of neurons at the injection site, as well as reduced Zif268 immunoreactivity in a distinct cortical zone around this cluster. C-fos or Fos-related immunoreactivity was decreased over widespread areas of frontoparietal and piriform cortex in epileptic rats, except for a focus at the injection site which, in most cases, showed increases in Fos-like immunoreactivity. Some epileptic rats showed increased Zif268 immunoreactivity in neurons of the ipsilateral ventral lateral and central lateral thalamic nuclei and increased Zif268 and Fos-like immunoreactivity in the pontine nuclei. Rats perfused before onset of seizures, showed no overt changes other than a slight decrease in Zif268 and Fos-like immunoreactivity at the injection site. The reciprocal changes in Zif268 immunoreactive neurons in the epileptic focus and the immediate surround parallel changes in gene expression for a number of molecules important in epileptogenesis and suggest a state of functional disconnection of the epileptic focus from other cortical areas that may contribute to the development and maintenance of focal epilepsy.     

The expression of mRNAs for hepatocyte growth factor/scatter factor, its receptor c-met, and one of its activators tissue-type plasminogen activator show a systematic relationship in the developing and adult cerebral cortex and hippocampus

The temporal and spatial expression in brain of the mRNAs for the pleiotropic cytokine hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-met were compared to those of a known HGF/SF activator, tissue-type plasminogen activator (tPA). In addition to the previously described expression in the developing and adult olfactory system [D.P. Thewke, N.W. Seeds, Expression of hepatocyte growth factor/scatter factor, its receptor, c-met, and tissue-type plasminogen activator during development of the murine olfactory system, J. Neurosci. 16 (1996) 6933–6944] two other regions of the mouse brain were found where the expression of tPA mRNA appeared to co-localized with HGF/SF and/or c-met mRNA. In the developing hippocampus, tPA mRNA was expressed coincident with HGF/SF and c-met mRNAs in the CA1 field. tPA mRNA was expressed in all areas of the adult hippocampus, while HGF/SF expression was restricted to the CA2 and CA3 fields, and c-met mRNA was seen primarily in the CA1 field. In the developing cerebral cortex, the expression of tPA mRNA was observed in the subplate and inner cortical plate between two layers of c-met expression, whereas HGF/SF mRNA was localized to the proliferative zone lining the lateral ventricle. Layer specific expression of both HGF/SF and c-met mRNA were observed in the adult cortex, where HGF/SF was expressed in layers IV and V and c-met in layers II–III, IV and V. The expression of tPA mRNA in the adult cortex was low and not layer specific, although homogenates of adult cortex did have detectable levels of tPA activity when subjected to zymography. Immunohistochemical analysis using HGF/SF and c-met antibodies on adult brain sections showed a distribution similar to the in situ hybridization results. C-met antibodies appeared to stain large neurons in the cortex and hippocampus. These results are consistent with the hypothesis that HGF/SF plays a role in the development and maintenance of both the cerebral cortex and hippocampus, and that tPA may act as a regulator of HGF/SF activity in these structures.     

Neonatal transection of the infraorbital nerve increases the expression of proteins related to neuronal death in the principal sensory nucleus of the trigeminal nerve

Neonatal lesion of the primary afferents in the infraorbital nerve causes the death of one-third of the neurons in the second-order target, the principal sensory nucleus of the trigeminal nerve (PSN). We examined the expression of two candidate `death' proteins, p53 and the antigen recognized by the antibody ALZ-50, in the normal and deafferented PSN. In addition, the effect of neonatal transection of the infraorbital nerve (a major component of the trigeminal nerve) on protein expression was examined. The expression of c-fos in the developing PSN was also studied as an index of metabolic activity. Protein expression was measured using quantitative analyses of immunoblots and immunohistochemical preparations. The expression of p53- and ALZ-50-immunoreactivity in the normal PSN peaked during the first postnatal week. Transection of the infraorbital nerve directly affected the expression of p53 and the ALZ-50-positive antigen. The immunoblots showed that whereas p53 amounts were unaffected by the lesion, ALZ-50 expression was significantly upregulated in the ipsilateral PSN 2 h and 2 days postlesion. The density of p53- and ALZ-50-immunoreactive neurons was significantly higher in the ventral ipsilateral PSN (i.e., the target of the transected infraorbital nerve) than in the contralateral PSN. c-fos expression selectively and transiently rose in the ventral ipsilateral PSN within 2 h of the lesion. Thus, both p53 and the ALZ-50-positive antigen are involved in neuronal death. In light of data suggesting that ALZ-50 recognizes a phosphorylated form of p53, we conclude that neuronal death in the developing nervous system involves the post-translational modification of an existing protein, p53. The increase in ALZ-50 expression apparently occurs during a catabolic phase of neuronal death, as indicated by the increase in c-fos expression.     

Induction of the c-fos proto-oncogene during opiate withdrawal in the locus coeruleus and other regions of rat brain

Opiate regulation of the nuclear proto-oncogene c-fos was studied in the locus coeruleus (LC) and other regions of rat brain by immunoblotting, northern blotting, and in situ hybridization procedures. Precipitation of opiate withdrawal in rats, which is known to increase LC firing rates 4-fold, led to a two- to three-fold increase in levels of mRNA and protein for c-fos in the LC 1–2 h after initiation of withdrawal. In contrast, levels of c-fos expression were decreased in LC from rats treated acutely or chronically with morphine but not experiencing withdrawal, conditions under which LC firing rate are depressed. Similar regulation of c-fos expression during opiate withdrawal was found in the amygdala, ventral tegmentum, nucleus accumbens, neostriatum, and cerebral cortex, but not in a number of other brain regions studied, which included the hippocampus, dorsal raphe, periaqueductal gray, and paragigantocellularis. In the LC and some other brain regions, induction of c-fos during opiate withdrawal was associated with a parallel induction of c-jun, another nuclear proto-oncogene, which, like c-fos, is expressed rapidly in brain in response to certain extracellular stimuli. The results demonstrate a novel use of c-fos in neuropharmacology, namely to map neuronal pathways and neuronal cell types activated in response to acute and chronic opiate administration and during opiate withdrawal, as well as in response to other psychotropic drug treatments.     

Amplification and expression of the epidermal growth factor receptor gene during the progression of neuroepithelial tumours in vivo

Summary The epidermal growth factor receptor (EGFR) gene is homologous to the oncogene c-erbB. The occurrence of amplification and rearrangements at the EGFR gene locus is associated with malignancy in neuroepithelial tumours. Sixteen neuroepithelial tumours from eight patients with recurrence of their neoplasms were analysed for changes at the EGFR gene locus and for expression of EGFR. Ten tumours from five patients lacked changes at the EGFR gene locus. Three of eight individuals showed EGFR gene amplifications in both tumours with a higher grade of amplification in the second tumour. In addition to amplification, a rearrangement was found in both tumours of the first patient. In the second case an amplification of chromosome-7-specific c-met sequences was found in the regrown tumour, suggesting that a polysomy 7 was at least partly responsible for the higher copy number of the EGFR sequences. In both tumours of the third patient with EGFR gene amplification different alleles were amplified. In contrast to the findings at the DNA level the EGFR expression, analysed by immunohistochemical techniques, showed a more heterogeneous pattern after tumour progression.