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PubMed1994

Identification of upstream signals regulating interleukin-6 gene expression during in vitro treatment of human B cells with pokeweed mitogen.

The present studies have characterized the regulation of interleukin-6 (IL-6) gene expression during pokeweed mitogen (PWM)-driven human B-cell differentiation. PWM induced an early and transient increase in the expression of immediate-early response genes of the jun/fos leucine zipper family (c-jun, jun B, c-fos, and fos-B). The induction of c-jun mRNA by PWM was concentration dependent. Nuclear run-on assays showed that PWM treatment is associated with an increased rate of c-jun gene transcription. The induction of c-jun mRNA precedes the induction of IL-6 gene expression and IL-6 secretion by the B cells. c-Jun antisense, but not sense, oligodeoxynucleotide (ODN) significantly decreases PWM-related B-cell (1) proliferation; (2) IL-6 mRNA induction; (3) IL-6 secretion; and (4) nuclear extract binding to AP-1 in electrophoretic mobility shift assay. In contrast, c-Fos anti-sense ODN did not effect either IL-6 mRNA induction or IL-6 secretion triggered in B cells by PWM. The results further show activation of c-Raf-1 kinase in PWM-treated B cells. Raf-1 acts upstream to mitogen-activated protein (MAP) kinase; therefore, studies were performed to assay for MAP kinase activation in these cells. The results show an increase in phosphorylation of myelin basic protein (MBP) and c-Jun "Y" peptide in PWM-treated B cells. Taken together, these findings suggest that PWM is able to initiate an intracytoplasmic signaling cascade in normal human splenic B cells, which, at least in part, involves serine/threonine protein kinases. These results show transient induction of immediate-early response genes in B cells and support a potential role for the c-jun gene product in regulation of IL-6 transcription and secretion.

B-Lymphocytes↗

PubMed1996

Overexpression of the proto-oncogene c-jun in association with low-risk type specific human papillomavirus infection in condyloma acuminata.

Infection with different types of human papillomavirus (HPV) is associated with neoplasia at different anatomic sites. The "low-risk" HPVs (LR-HPV) are responsible for benign genital lesions such as condyloma acuminata. In order to clarify the tumorigenic mechanism of LR-HPV, the HPV infection status was investigated and the expression of the c-jun proto-oncogene in different HPV-related skin and genital lesions analyzed. Of the 17 condyloma specimens analyzed by Western blotting, 13 cases (76.5%) exhibited overexpression of the c-jun gene. All 13 cases harbored high copy numbers of the LR-HPV genome with an average of 926 copies per cell, whereas the other four cases had an average of 12 copies of LR-HPV per cell (P < 0.001). Further typing of HPV by Southern blotting revealed that HPV-6 and HPV-11 infections predominated in c-jun positive cases. The c-jun protein was detected much less frequently in cervical cancers (three of 29, or 10.3%) and skin warts (one of 10), and was not detected in five genital polyps or in five normal cervical tissues. These findings suggest a type 6/11-specific induction of c-jun gene expression in HPV-related neoplastic lesions.

Animals↗

PubMed2000

Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase.

Ca(2+)-sensitive tyrosine kinase Pyk2 was shown to be involved in angiotensin (Ang) II-mediated activation of extracellular signal-regulated kinase (ERK) via transactivation of epidermal growth factor receptor (EGF-R). In this study, we tested the involvement of Pyk2 and EGF-R in Ang II-induced activation of JNK and c-Jun in cardiac fibroblasts. Ang II markedly stimulated JNK activities, which were abolished by genistein and intracellular Ca(2+) chelators but partially by protein kinase C depletion. Inhibition of EGF-R did not affect Pyk2 and JNK activation by Ang II. Stable transfection with a dominant negative (DN) mutant for Pyk2 (PKM) completely blocked JNK activation by Ang II. DN mutants of Rac1 (DN-Rac1) and MEK kinase (DN-MEKK1) also abolished it, whereas those of Cdc42, RhoA, and Ha-Ras had no effect. Induction of c-Jun gene transcription by Ang II was abolished in PKM, DN-Rac1, and DN-MEKK1, in which Ang II-induced binding of ATF2/c-Jun heterodimer to the activator protein-1 sequence at -190 played a key role. These results suggest that 1) in cardiac fibroblasts activation of JNK and c-Jun by Ang II is initiated by Pyk2-dependent signalings but not by downstream signals of EGF-R or Ras, 2) Rac1 but not Cdc42 is required for JNK activation by Ang II upstream of MEKK1, and 3) ATF-2/c-Jun binding to the activator protein-1 sequence at -190 plays a key role for induction of c-Jun gene by Ang II.

Angiotensin II↗

PubMed1995

Increases in nup475 and c-jun are early molecular events that precede the adaptive hyperplastic response after small bowel resection.

OBJECTIVE: The authors determined whether increases of nup475 and c-jun gene expression occur after small bowel resection and whether these changes are specific to the gut. SUMMARY BACKGROUND DATA: Massive small bowel resection (SBR) is characterized by adaptive proliferation of the remaining gut mucosa; the molecular signals responsible for this adaptive hyperplasia are unknown. Increases in the "immediate-early genes" nup475 and c-jun are noted in some proliferating tissues; however, alterations in the expression of these genes have not been described in the gut after SBR. METHODS: Rats underwent either a 70% proximal SBR or intestinal transection with reanastomosis (SHAM) and were then killed over a time course (0.5, 2, and 24 hours). The ileum, duodenum, colon, and kidneys were removed and RNA was extracted for Northern hybridization. RESULTS: The authors found that steady-state mRNA levels of both nup475 and c-jun were increased 81% and 62%, respectively, in the ileal remnant at 2 hours in rats after SBR compared with the SHAM group. In addition, nup475 was increased 101% in the duodenum at 24 hours and 31% in the colon at 0.5 hours in rats after SBR. In contrast, neither gene was increased in the kidney. CONCLUSIONS: Increases in steady-state levels of nup475 and c-jun are limited to the gut after SBR, and the timing and magnitude of these changes differ, depending on the gut segment. Finally, the rapid and nutrient-independent increases of nup475 and c-jun suggest an important role for these genes as early molecular signals that participate in the adaptive hyperplasia occurring in the gut remnant after SBR.

Adaptation, Physiological↗

PubMed2000

Interaction between the serotoninergic and dopaminergic systems in d-fenfluramine-induced activation of c-fos and jun B genes in rat striatal neurons.

To test for the relative contributions of the dopaminergic and serotoninergic systems in the striatum to the effects of d-fenfluramine, an indirect serotonin receptor agonist, we assessed the expression of Fos/Jun proteins induced by d-fenfluramine given alone or in the presence of dopaminergic or serotoninergic agents. To determine the neuronal targets of d-fenfluramine in the striatum, we identified the phenotypes of striatal neurons in which d-fenfluramine induced Fos expression. Our results demonstrated that d-fenfluramine evokes nuclear expression of Fos/Jun B proteins in the striatum, and that the Fos expression was dose-dependent and accompanied by transient induction of c-fos mRNA. Fos expression was blocked by p-chloroamphetamine, a serotoninergic neurotoxin. Pretreatment with SCH 23390, a D1-dopamine receptor antagonist, led to a marked decrease in Fos/Jun B expression in the caudoputamen, but not in the cortex, whereas pretreatment with methiothepin, a nonselective serotonin 5-HT1 receptor antagonist, blocked Fos expression completely in the cortex and only partially in the caudoputamen. The expression of Fos/Jun B in the striatum occurred mainly in dynorphin-containing neurons and in a subpopulation of striatal interneurons that exhibited NADPH-diaphorase activity. Most of the enkephalin-containing neurons of the striatum did not show Fos/Jun B staining. These results suggest that the mechanism by which d-fenfluramine induces c-fos and jun B expression in the rat caudoputamen depends at least in part on activation of the dopaminergic system by serotonin.

Animals↗

PubMed1994

Transcriptional and posttranscriptional mechanisms involved in the interleukin-1, steroid, and protein kinase C regulation of nerve growth factor in cortical astrocytes.

Neonatal rat cortical astrocytes in primary culture synthesize and secrete nerve growth factor (NGF). Treatment of astrocytes with interleukin-1 beta (IL-1) or the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) increased NGF mRNA content by six- to 10-fold, followed in time by increases in cell content and cell secretion of NGF. Dexamethasone potently inhibited the effects of IL-1 and TPA on astroglial cell NGF expression. The action of IL-1 was not mediated by PKC because treatment of cells with maximal concentrations of both IL-1 and TPA gave an additive increase in NGF mRNA content and NGF secretion, and because down-regulating PKC activity failed to inhibit the stimulatory effects of IL-1. Moreover, both agents increased NGF gene transcription in nuclear run-on assays, but only IL-1 significantly stabilized the NGF mRNA. An analysis of the effects of IL-1 and TPA on immediate early gene expression indicated that IL-1 preferentially induced c-jun gene expression, whereas TPA greatly increased c-fos and zif/268 gene expression. These results suggest that IL-1 activates c-jun and NGF gene expression, and NGF mRNA stabilization in astrocytes by a distinct PKC-independent signaling pathway.

Animals↗

PubMed2006

Cytoskeletal and cell contact control of the glucocorticoid pathway.

The cytoskeleton is a dynamic network that undergoes restructuring during a variety of cellular events including cell contact formation, cell invasion and the mitotic phase of the cell cycle. Here, we review the contribution of the cytoskeletal network to the inductive activity of glucocorticoids by focusing on the hormonal control of glutamine synthetase in the chick neural retina. Depolymerization of the cytoskeleton in cells of the intact retinal tissue inhibits the hormonal induction of glutamine synthetase, but does not alter the cellular amount of the glucocorticoid-receptor protein or the ability of the receptor molecules to translocate into the nucleus. Inhibition of glutamine synthetase induction occurs via a mechanism that involves elevation of c-Jun protein accumulation and repression of glucocorticoid-receptor transcriptional activity. Unlike growth factors and other c-Jun inducing stimuli that control the transcription of the c-Jun gene, depolymerization of the cytoskeleton elevates c-Jun accumulation by upregulating the translation of the c-Jun transcript. We postulate that the cytoskeletal-dependent increase in c-Jun accumulation is involved in cell contact control of both cell proliferation and transcriptional activity of the glucocorticoid-receptor protein.

Animals↗

PubMed1998

Rapid and long-lasting suppression of the ATF-2 transcription factor is a common response to neuronal injury.

The activating transcription factor 2 (ATF-2) protein, a neuronal constitutively expressed CRE-binding transcription factor, is essential for the intact development of the mammalian brain. ATF-2 is activated by c-Jun N-terminal kinases and modulates both the induction of the c-jun gene and the function of the c-Jun protein, a mediator of neuronal death and survival. Here we show by immunocytochemistry and Western blotting that ATF-2 is rapidly suppressed in neurons within 1-4 h following neuronal stress such as transient focal ischemia by occlusion of the medial cerebral artery, mechanical injury of the neuroparenchym, stimulation of adult dorsal root ganglion neurons in vitro by doxorubicin as well as within 24 h following nerve fiber transection. ATF-2 reappears and regains basal levels between 12 h and 72 h following ischemia, between 50 and 100 days following axotomy, but remains absent around the site of mechanical injury during the process of degeneration. Following ischemia and tissue injury, ATF-2-IR also disappeared in areas remote from the affected brain compartments indicating the regulation of its expression by diffusible molecules. These findings demonstrate that the rapid and persistent down-regulation of ATF-2 is a constituent of the long-term neuronal stress response and that the reappearance of ATF-2 after weeks is a marker for the normalization of neuronal gene transcription following brain injury.

Activating Transcription Factor 2↗

PubMed1992

Transcriptional activation of jun and actin genes by estrogen during mitogenic stimulation of rat uterine cells.

Estrogens induce transcriptional activation of c-fos and c-myc proto-oncogenes during mitogenic stimulation of human, chicken, mouse and rat cells in vivo and in vitro. In this paper we show that 17 beta-estradiol injected into adult ovariectomized rats increases c-jun, jun-B and jun-D gene transcription in the uterus. Kinetics and amplitude of response are different for each gene, since c-jun is activated first, within 30 min after injection, followed by jun-D and jun-B, 60 and 90 min after injection, respectively. Maximal activation of jun-B marks a drop in transcription of all the jun genes. Furthermore, transcriptional activation by 17 beta-estradiol of the growth-regulated beta- and gamma-cytoskeletal actin genes is prevented by an inhibitor of protein synthesis, indicating that it is a secondary response to the hormone. These data support the hypothesis that during growth stimulation of target cells the estrogen receptor induces transcription of regulatory genes, triggering in this way a cascade of gene regulation events that results in progression through the cell cycle.

Actins↗

PubMed1994

Tumorigenic and metastatic properties of two ras-oncogene transfected rat fibrosarcoma cell lines defective in c-jun.

We here report the spontaneous loss of both homologues of the c-jun gene in two cell lines, isolated after transfection of rat embryo fibroblasts with single ras-oncogenes. These cells lines (designated A14 and B25) grow rapidly in vitro, have transformed morphologies and are invasive through reconstituted basal membranes. Both c-jun defective cell lines were found to be tumorigenic and metastatic in athymic mice. Loss of c-jun was paralleled by a dramatic decrease in interstitial collagenase expression, whereas stromelysin mRNA expression in c-jun- A14 and B25 cells was similar to that observed in c-jun+ transformed cell lines. Transient transfection experiments using reporter plasmids showed that stromelysin promoter activity in A14 cells was severely impaired by a point mutation in the -71 to -65 AP-1 motif, and was inhibited by a Jun dominant negative mutant. Gel mobility shift studies demonstrated the presence of a factor in A14 nuclear extracts capable of binding the stromelysin TRE. This factor bound JunB, JunD and Fos antibodies. Our findings suggest that c-Jun is not required for the tumorigenic and metastatic potential of ras-transformed fibrosarcoma cells, and that AP-1 protein(s) lacking c-Jun are capable of activating the stromelysin gene promoter.

Animals↗

PubMed1993

Hormonal regulation and expression of the jun-D protooncogene in specific cell types of the rat uterus.

Steroid hormone regulation and cell-type specific expression of the jun-D protooncogene in rat uterus was examined. Adult, ovariectomized rats were injected with progesterone, testosterone, 17beta-estradiol (E2-17beta), 16alpha-estradiol (E2-16alpha), dexamethasone or cycloheximide. Uteri were collected between 0 and 6 h post-treatment. Northern blot analysis of uterine RNA revealed that induction of jun-D was specific for estrogenic steroids, as progesterone and testosterone had no effect on expression of this member of the jun gene family. Treatment with E2-17beta increased jun-D mRNA levels by approx. 5-fold, with expression reaching peak levels at 3 h after treatment and declining thereafter. Administration of E2-16alpha, a short-acting estrogen that does not cause uterine cell proliferation, increased expression of jun-D but with different kinetics compared to the long-acting E2-17beta. The mRNA levels of jun-D increased by 3-fold 1 h after administration of E2-16alpha but declined soon after. Slight induction of jun-D mRNA by dexamethasone was apparent, but to a much lesser extent compared to estrogen. The protein synthesis inhibitor, cycloheximide, did not block jun-D induction, indicating that this is an "immediate early" response. Expression of Jun-D protein was examined by immunohistochemical methods. E2-17beta treatment activated jun-D primarily in the nuclei of luminal and glandular epithelial cells of the endometrium. These results demonstrate that hormonal induction of jun-D is specific for estrogens and that uterine expression of this protooncogene occurs in a cell-type specific manner.

Animals↗

PubMed1992

Effects of ionizing radiation and beta-adrenergic stimulation on the expression of early response genes in rat parotid glands.

There is little known about the regulation of gene expression in rat parotid glands after exposure to ionizing radiation. The present studies investigate the effects of in vivo ionizing radiation, with subsequent stimulation of beta-adrenergic receptors by isoproterenol, on parotid gland function and on the expression of the early response genes, c-fos, c-jun, and jun B. Ionizing radiation diminished parotid gland weight and saliva output. Treatment of irradiated rats with isoproterenol increased the gland weight to levels similar to those in nonirradiated rats. However, such treatment had no effect on saliva output as indicated by measurements of parotid salivary flow rate. Irradiation alone increased the expression of c-fos, c-jun, and jun B. The combination of irradiation and isoproterenol had an additional effect on the levels of c-fos and jun B mRNAs and proteins particularly at earlier experimental times (1 to 8 h). Isoproterenol alone induced high levels of c-fos and jun B mRNA but not of c-jun mRNA. However, c-jun mRNA was induced markedly by radiation and 8 h of isoproterenol treatment, indicating a combined effect on c-jun gene expression. These observations suggest that the expression of the proto-oncogenes c-fos, c-jun, and jun B is probably regulated through differential signal transduction pathways which may be activated by these external stimuli and may be associated with functional changes induced in the rat parotid gland by ionizing radiation and by ionizing radiation and isoproterenol.

Animals↗

PubMedDate not supplied

Degradation of constitutive transcription factors during apoptosis in rat thymocytes.

Dexamethasone (Dex) accelerates the rate of apoptosis in thymocytes by a process thought to require gene expression. Among the genes implicated in the regulation of this phenomenon are the immediate early genes such as c-fos and c-jun, whose expression is modulated by a complement of preexisting transcription factors. We have analyzed the DNA-binding activity of these constitutive transcription factors during Dex-induced apoptosis in thymocytes to assess their functionality. We observed a progressive loss of the DNA-binding proteins in parallel with the appearance of the characteristic morphological and biochemical features of apoptosis. At the same time we have found a general increase in the nuclear proteolytic activity concomitant with a significant loss of the nuclear nonhistone chromosomal proteins. Indeed, cotreatment of thymocytes with the nonspecific serine protease inhibitor phenylmethylsulphonyl fluoride was able to partially protect the stability of the DNA-binding proteins and alter the expression of the c-fos and c-jun genes but did not inhibit apoptosis. Our results suggest that the action of a protease(s) is responsible for the degradation of constitutive transcription factors during Dex-induced apoptosis, rendering the death pathway irreversible.

Animals↗

PubMed1998

Regulation of c-Jun NH2-terminal kinases in isolated canine gastric parietal cells.

c-Jun NH2-terminal kinases (JNKs) are protein kinases that are activated by a wide variety of extracellular signals. This study investigated the expression and regulation of JNKs in isolated gastric canine parietal cells. Western blot analysis of cell lysates from highly purified (>95%) parietal cells with an antibody recognizing JNK1 and to a lesser degree JNK2 revealed the presence of two bands of 46 and 54 kDa, respectively. JNK1 activity was quantitated by immunoprecipitation and in-gel kinase assays. Of the different agents tested, carbachol was the most potent inducer of JNK1 activity, whereas histamine and epidermal growth factor induced weaker responses. The proinflammatory cytokine tumor necrosis factor-alpha stimulated JNK1 but had no effect on extracellular signal-regulated kinase (ERK2) induction, suggesting that activation of JNK1 might represent an important event in mediation of the inflammatory response in the stomach. The action of carbachol was dose (0.1-100 microM) and time dependent, with a maximal stimulatory effect (fourfold) detected after 30 min of incubation and sustained for 2 h. Addition of the specific protein kinase C (PKC) inhibitor GF109203X did not affect the stimulatory action of carbachol. The intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid-AM inhibited carbachol induction of JNK1 activity by 60%. Thapsigargin (1 microM), an intracellular Ca2+-rising agent, induced JNK1 activity more than threefold. Carbachol activation of JNK1 resulted in induction of c-Jun (protein) transcriptional activity and in stimulation of parietal cell mRNA content of c-jun. In conclusion, our data indicate that carbachol induces JNK activity in gastric parietal cells via intracellular Ca2+-dependent, PKC-independent pathways, leading to induction of c-jun gene expression via phosphorylation and transcriptional activation of c-Jun.

Animals↗

PubMed1994

Elevated expression of the junB proto-oncogene is essential for v-fos induced transformation of Rat-1 cells.

We previously described the isolation of non-tumorigenic revertants from mutagenized populations of v-fos-transformed Rat-1 cells (Zarbl et al., 1987). In the present study we examined the possibility that the revertant phenotype resulted from mutations that altered the expression or activities of the c-jun or junB proto-oncogenes. The results demonstrated that levels of the c-jun mRNA and protein were unchanged in the revertants when compared to the transformed parental cells, and ectopic overexpression of c-jun failed to retransform the revertants. Although one mutant allele was detected in revertant EMS-1-19, overexpression of this mutant allele failed to inhibit v-fos induced cell transformation. Together these results indicated that the revertant phenotype did not result from altered expression or mutations in the c-jun gene. In contrast to the results obtained with c-jun, the levels of junB mRNA and protein were found to be reduced two- or threefold in revertant EMS-1-19. Ectopic overexpression of junB induced transformation of revertant EMS-1-19, but failed to transform Rat-1 cells. Moreover, about 10% of v-fos transformed cells transfected with vectors that express antisense junB mRNA acquired a non-transformed phenotype. Together these results indicate that expression of junB above a threshold level is essential for v-fos-induced transformation of Rat-1 fibroblasts.

Alleles↗

PubMed2004

Expressions of junB and c-fos are enhanced in 4-nitroquinoline 1-oxide-induced rat tongue cancers.

Activator protein-1 (AP-1) is a transcription factor activated in many tumors. Using 4-nitroquinoline 1-oxide (4NQO)-induced rat tongue cancers (TC), the present study investigated the expression levels of genes that encode the components of AP-1, the jun gene family (c-jun, junB and junD) and the fos gene family (c-fos, fra-1, fra-2 and fosB). Expression levels of junB and c-fos mRNAs in TC were significantly elevated compared with those in epithelial tissue of control rat tongue, although only c-fos mRNA levels tended to be elevated in dysplastic tongue epithelium. Histologically, all 4NQO-induced rat TC were well-differentiated squamous cell carcinomas. Immunostaining for JunB and c-Fos proteins was positive in the nuclei of tumor cells of all TC. It is noteworthy that JunB was negative, but c-Fos was positive in the dysplastic tongue epithelium of the 4NQO-treated rats. Immunostaining for both proteins was negative in tongue mucosal epithelium of control rats. There were no mutations in the coding regions of either junB or c-fos in all the TC examined. These results suggest the possibility that the expressions of junB and c-fos were enhanced stepwise in 4NQO-induced carcinogenesis of rat tongue, and that the coexpression of JunB and c-Fos might play an important role in the establishment of TC.

4-Nitroquinoline-1-oxide↗

PubMed1991

Jun inhibits myogenic differentiation.

Myoblasts from skeletal muscle of chicken or Japanese quail embryos were infected with avian sarcoma virus 17 (ASV-17), a retrovirus carrying the jun oncogene. At high multiplicities of infection ASV-17-induced morphologic transformation inhibited fusion of myoblasts into myotubes and stimulated extended replication. The expression of the muscle-specific proteins desmin, myosin and creatine phosphokinase was inhibited in ASV-17-infected cultures. Immunofluorescent staining detected strong expression of the ASV-17 Gag-Jun fusion protein in the nuclei of infected mononuclear myoblasts, but Gag-Jun was not detectable in multinucleated myotubes that occurred in clonal populations of ASV-17-infected quail myoblasts. This result suggests that the nuclear expression of viral jun and myogenic differentiation are mutually exclusive events. A mutant of ASV-17, ts jun-1, is partly temperature-sensitive in its ability to transform chicken embryo fibroblasts. At the non-permissive temperature of 41.5 degrees C, multinucleated myotubes readily formed in ts jun-1-infected myoblast cultures and expressed muscle-specific proteins detectable by immunofluorescent staining. These myotubes also showed strong immunofluorescent staining for Gag-Jun in the cell nuclei. The nuclear expression of a Jun protein that is defective in its transforming function appears therefore to be compatible with myogenesis. Several retroviral constructs carrying various viral and cellular jun inserts, as well as jun deletion mutants and recombinants between c-jun and v-jun, were tested for their effect on myogenic differentiation. There was an approximate correlation between the ability of a construct to transform chicken embryo fibroblasts and its effectiveness in interfering with myogenic differentiation. We conclude that the expression of an oncogenic jun gene in myoblasts strongly inhibits myogenic differentiation, and that a highly transforming Jun protein cannot be expressed in the nuclei of differentiating myotubes, while the presence of transformation-defective variants of Jun is compatible with differentiation.

Animals↗

PubMed2001

Sequential up-regulation of the c-fos, c-jun and bax genes in the cortex, striatum and cerebellum induced by a single injection of a low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6 mice.

We investigated whether single injection of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) (20 mg/kg) will alter the expression of pro-apoptotic genes, namely, the c-fos, c-jun, and bax, in the striatum, cortex, and cerebellum of adult male C57BL/6 mice using reverse transcription-polymerase chain reaction assay. Injection of MPTP induced a transient decrease in the content of tyrosine hydroxylase estimated by the immunoreactivity in the striatum, which completely recovered 14 day after injection. A rapid but transient up-regulation of c-fos and c-jun genes occurred an hour after MPTP-injection, and a delayed but persistent up-regulation of bax gene expression occurred 3 day after injection. The up-regulation of these genes was present in all the examined brain regions. This result suggests that MPTP, at a low dose causing transient degeneration in the striatum, is capable of triggering two genetic pathways related to the generation of apoptosis in both dopaminergic and non-dopaminergic systems in the mouse brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗