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PubMed1998

The induction of apoptosis by SV40 T antigen correlates with c-jun overexpression.

Simian virus (SV40) T antigen shares many characteristics with adenovirus E1A which is known to induce apoptosis. To verify the potential of SV40 T antigen-mediated apoptosis, we stably expressed T antigen in immortalized human epithelial cells (Z172 and HaCaT). We found that SV40 T antigen could directly cause apoptosis in 22-27% of these cells under normal growth condition as measured by chromatin condensation and nucleosomal fragmentation. The apoptosis of HaCaT cells which contain mutant p53 suggests the p53-independent nature of T antigen-mediated apoptosis. T antigen-induced apoptosis was associated with increased expression of c-Jun protein. Moreover, the overexpression of c-jun alone in these cells also induced apoptosis, indicating that c-jun might play an important role in T antigen-induced apoptosis.

Adenovirus E1A Proteins↗

PubMed1998

Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor.

We used KO mice lacking either TNF receptor 1 (TNFR-1) or receptor 2 (TNFR-2) to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves only one or both TNF receptors and to analyze in more detail the abnormalities caused by lack of TNFR-1 receptor, which is required for the initiation of liver regeneration. Lack of TNFR-2 had little effect on NF-kappaB and STAT3 binding, and no effect in interleukin-6 production after PH, but caused a delay in AP-1 and C/EBP binding and in the expression of c-jun and c-myc messenger RNA (mRNA). In contrast to mice lacking TNFR-1, which had deficient hepatocyte DNA synthesis and massive lipid accumulation in hepatocytes, TNFR-2 KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. We conclude that TNFR-1, but not TNFR-2, is necessary for liver regeneration, and that NF-kappaB and STAT3 binding are activated by signals transduced by TNFR-1. Inhibition of AP-1 and C/EBP binding and in the expression of c-jun and c-myc mRNA in the first 4 hours after PH, as well as the apparent lack of Fos in AP-1 complexes, had no effect on the timing or extent of DNA replication.

Animals↗

PubMed1989

jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun.

We have cloned the human jun-B gene and determined its sequence and transforming and trans-activating activities. jun-B is less potent that c-jun in transforming and immortalizing primary rat embryo cells in cooperation with activated ras (effects enhanced by c-fos and TPA); unlike c-jun, jun-B does not transform Rat-1A cells alone. However, cotransfection of c-jun and jun-B into primary rat embryo cells with c-Ha-ras results in a significant decrease in transformation compared with c-jun alone, an event reversed by TPA. Cotransfection of c-jun and jun-B with or without c-fos into F9 teratocarcinoma cells results in decreased trans-activation of AP-1 compared with either gene alone. Introduction of jun-B into primary rat c-jun/ras transformants or c-jun into jun-B/ras transformants also results in a decrease in trans-activation. These findings demonstrate that, whereas jun-B and c-jun each participate in AP-1 trans-activation and malignant transformation, interactions between them involve negative regulation.

Amino Acid Sequence↗

PubMed1992

[An unusual leucine motif in amino acid sequences of subunit 9 of ATP-synthase from plant mitochondria, modified by mRNA editing].

The amino acid sequences of subunit 9 of plant mitochondrial ATP-synthase contain a leucine motif which differs from the leucine repeat earlier detected within the composition of proteinaceous products of Myc, Fos, and Jun proto-oncogens. The structural organization of this repeat in proteolipid sequences can be modified via transformation of serine triplets into leucine ones as a result of editing of an appropriate mRNA.

Amino Acid Sequence↗

PubMed1993

Utility of a C-jun microsatellite marker in determining gene dosage for fatty (fa).

The Zucker fatty (fa) mutation provides a genetic model for obesity and non-insulin dependent diabetes mellitus. The molecular pathogenesis of the metabolic phenotype of these animals is not known. Detailed molecular maps of the region surrounding the fa locus on rat chromosome 5 can be used for positional cloning experiments as well as to permit genotyping of animals from appropriate crosses before the confounding metabolic effects of obesity have occurred. We describe the development of a polymerase chain reaction (PCR) assay for a polymorphic simple sequence repeat (SSR) in the promoter region of the protooncogene c-Jun. This assay was used to position c-Jun 4.5cM proximal to the fa locus in 111 F2 progeny of a 13MBN fa/+ F1 intercross. Concurrent use of the c-Jun SSR with a previously described assay for a microsatellite in the glucose transporter, Glut1, permits rapid and accurate assessment of genotypes at the fa locus in animals of any age using minimal amounts of DNA. A strategy is described which minimizes the error rate in assigning genotype at the fatty locus for backcross and intercross progeny.

Animals↗

PubMed1991

v-erbA oncogene abrogates growth inhibition of chicken embryo fibroblasts induced by retinoic acid.

Retinoic acid inhibits chicken embryo fibroblast (CEF) proliferation by altering the G1 phase of the cell cycle with induction of a strong increase in the generation time. This growth-inhibitory response to retinoic acid is abrogated by expression of the v-erbA oncogene, suggesting an interference between retinoic acid receptors and the v-ErbA oncoprotein. Moreover, CEF expressing either the v-src, v-jun or v-fos oncogenes are also insensitive to retinoic acid treatment. In contrast, CEF expressing either the v-myc, v-myb-ets, v-mil, v-sea or v-erbB oncogenes are still sensitive to retinoic acid. These data strongly suggest functional interferences between the retinoic acid receptors and the AP-1 transcription factor complex in the control of expression of genes involved in CEF proliferation.

Animals↗

PubMedDate not supplied

Differential oncogene expression and susceptibility to apoptosis in the human leukemia HL60 cell lines: implications for etoposide resistance.

Mechanisms of etoposide (VP-16) resistance have been evaluated in a human promyelocytic leukemia HL60 cell line. HL60 resistant (HL60/AR) cells were selected for resistance with adriamycin and were 250-fold resistant to VP-16. We have found that while a significantly higher (10 to 15-fold more) dose of VP-16 was required to induce similar amounts of SDS-KCI-precipitable DNA-protein complex formation in the resistant cell line, there was no difference in the repair of VP-16-induced DNA damage, indicating that differential DNA repair was not involved in VP-16 resistance in HL60 cells. VP-16 treatment significantly inhibited c-myc expression and induced c-jun and c-fos expressions in sensitive cells. In contrast, VP-16 had no effect on c-myc, c-jun or c-fos expressions in resistant cells. The level of bcl2 oncogene was similar in both cell lines; however, treatment with VP-16 resulted in a time- and dose-dependent degradation of the genomic DNA into oligo-sized DNA only in the sensitive cells, indicating that differential expressions of oncogenes (c-myc, c-jun, and c-fos) and susceptibility to apoptosis may play important roles in the sensitivity and resistance to VP-16 in HL60 cells.

Apoptosis↗

PubMed1992

No correlation between ras, c-myc and c-jun proto-oncogene expression and prognosis in advanced carcinoma of cervix.

55 patients suffering from stage III or IV carcinoma of cervix were treated with two pulses of neo-adjuvant chemotherapy prior to radical radiotherapy. 51% (26/51) had a partial response. The initial response to chemotherapy is associated with significantly better long-term survival. The 3-year survival of chemotherapy responders is 62% against 21% for non-responders (P = 0.009 log-rank test). To detect possible differences in oncogene expression in biopsy specimens taken from responding and non-responding patients, paraffin-fixed material was immunocytochemically stained for the expression of the protein products of ras, c-myc and c-jun proto-oncogenes. The frequency of oncogene expression was ras 80.4%, c-myc 45.1% and c-jun 39.2%. There was no statistically significant association between oncogene expression, time to local recurrence or development of metastases or survival.

Adult↗

PubMed2004

Effect of deoxyribozymes targeting c-Jun on solid tumor growth and angiogenesis in rodents.

BACKGROUND: The basic region-leucine zipper protein c-Jun has been linked to cell proliferation, transformation, and apoptosis. However, a direct role for c-Jun in angiogenesis has not been shown. METHODS: We used human microvascular endothelial cells (HMEC-1) transfected with a DNAzyme targeting the c-Jun mRNA (Dz13), related oligonucleotides, or vehicle in in vitro models of microvascular endothelial cell proliferation, migration, chemoinvasion, and tubule formation, a rat model of corneal neovascularization, and a mouse model of solid tumor growth and vascular endothelial growth factor (VEGF)-induced angiogenesis. All statistical tests were two-sided. RESULTS: Compared with mock-transfected cells, HMEC-1 cells transfected with Dz13 expressed less c-Jun protein and possessed lower DNA-binding activity. Dz13 blocked endothelial cell proliferation, migration, chemoinvasion, and tubule formation. Dz13 inhibited the endothelial cell expression and proteolytic activity of MMP-2, a c-Jun-dependent gene. Dz13 inhibited VEGF-induced neovascularization in the rat cornea compared with vehicle control (Dz13 versus vehicle: 4.0 neovessels versus 30.7 neovessels, difference = 26.7 neovessels; P =.004; area occupied by new blood vessels for Dz13 versus vehicle: 0.35 mm2 versus 1.52 mm2, difference = 1.17 mm2; P =.005) as well as solid melanoma growth in mice (Dz13 versus vehicle at 14 days: 108 mm3 versus 283 mm3, difference = 175 mm3; P =.006) with greatly reduced vascular density (Dz13 versus vehicle: 30% versus 100%, difference = 70%; P<.001). CONCLUSION: DNAzymes targeting c-Jun may have therapeutic potential as inhibitors of tumor angiogenesis and growth.

Angiogenesis Inhibitors↗

PubMed1995

Reversion of v-H-ras-transformed NIH 3T3 cells by apigenin through inhibiting mitogen activated protein kinase and its downstream oncogenes.

Apigenin, a plant flavonoid, induced the reversion of transformed phenotypes of v-H-ras-transformed NIH 3T3 cells at a quite low concentration of 12.5 microM. In the present study, we have examined the components of this Ras-mediated signaling transduction to determine whether they were involved in the apigenin-induced reversion process. Interestingly, the consitutively activated mitogen activated protein kinase (MAPK) in the ras transformant was inhibited significantly and rapidly by 25 microM apigenin within 30 min, and this reduction continued for more than 4 h. Corroborating these observations, expression of the downstream oncogenes c-jun and c-fos was also dramatically reduced during the first 4 h of treatment. We found that the levels of ras protein and mRNA were not affected by 24 h of treatment with apigenin. These findings indicate that apigenin-induced reversion of v-H-ras-transformed NIH 3T3 cells may occur by inhibiting MAPK activity and its downstream oncogenes rather than by affecting the expression of the ras gene.

3T3 Cells↗

PubMed1994

In vitro and in vivo acceleration of the neoplastic phenotype of a low-tumorigenicity rat bladder carcinoma cell line by transfected transforming growth factor-alpha.

We conducted an experiment to determine whether expression of transforming growth factor-alpha (TGF-alpha) enhances tumorigenicity in a low-tumorigenicity rat bladder carcinoma cell line and whether it is sufficient to induce a tumorigenic phenotype in a nontumorigenic rat bladder cell line. D44c cells (which are nontumorigenic) were derived from a minute nodule from a bladder treated with N-methyl-N-nitrosourea (MNU); G1-200 cl-17 cells (which have low tumorigenicity) were isolated from D44c cells exposed to MNU in vitro. Neither cell line expressed TGF-alpha mRNA. The cells were cotransfected with pSV2neo and pSR alpha-rTGF-alpha. The latter plasmid contains the rat TGF-alpha cDNA under the transcriptional control of the SR alpha promoter. In the low-tumorigenicity G1-200 cl-17 cells, the expression of TGF-alpha mRNA and the subsequent synthesis of TGF-alpha protein activated epidermal growth factor receptors (EGFRs) and markedly enhanced tumorigenicity in nude mice (i.e., shortened the latency period before tumor appearance, accelerated the rate of growth, and increased the size of the tumors) as well as anchorage-independent growth in vitro. In nontumorigenic D44c cells, however, transfected TGF-alpha did not induce either anchorage-independent growth or tumorigenicity in nude mice, in spite of overexpression of EGFR mRNA and the constitutive expression of c-jun and junB mRNA. These results suggest that the increased signal transduction mediated by TGF-alpha enhanced tumorigenicity in a cell that was already tumorigenic but was not sufficient to induce tumorigenicity in a nontumorigenic cell.

Animals↗

PubMed1992

Effects of sialagogues on ornithine decarboxylase induction and proto-oncogene expression in murine parotid gland.

The mechanism of a sialagogue-induced increase in ornithine decarboxylase (ODC) activity and the expressions of proto-oncogenes in murine parotid gland were investigated by use of isoproterenol (IPR), carbachol (CC), and methoxamine (MTX). The results were as follows: (1) The three sialagogues had similar effects on the parotid in vivo (mouse parotid after a single injection of IPR) and/or in vitro (rat parotid explants cultured on siliconized lens paper floating on 199 medium containing IPR, CC, or MTX), the order of their effectiveness being IPR > CC > MTX. (2) Northern/dot and Western blot analyses revealed that the sialagogues elevated the steady-state levels of ODC mRNA and ODC protein to maxima at two h and six h, respectively, after stimulation. The increases were roughly proportional to those in ODC activity, suggesting that sialagogue-dependent enzyme induction is regulated at the transcriptional level. (3) The mRNAs of four of nine proto-oncogenes examined showed sialagogue-dependent increases to maxima at 30 min (c-fos) or 60 min (c-jun, c-myc, and c-src) after the beginning of stimulation. These increases were all transient, with the levels returning to the control values (without sialagogue) within 60 min. (4) The IPR-dependent elevations of ODC activity and the mRNAs of ODC, c-fos, and c-jun were inhibited by monensin, but not by polymyxin B. On the other hand, the CC-dependent increases in these parameters were inhibited by polymyxin B but not by monensin.(ABSTRACT TRUNCATED AT 250 WORDS)

Amanitins↗

PubMed1993

Molecular mechanism of cell death induced dNTP pool imbalance.

We have previously reported that treatment of the FM3A cells with 5-fluorodeoxyuridine (FdUrd) induced DNA double strand breaks and cell death. We proposed the hypothesis of dNTP pool imbalance death in order to understand these phenomena: intracellular dNTP pool imbalance induced by FdUrd would be a trigger for activation or induction of endonuclease which would attack DNA to cause double strand breaks and subsequent cell death. To observe the mechanism of dNTP imbalance death we have purified and characterized the endonuclease that was detected in FdUrd treated FM3A cells but not untreated cells. As the result, we suggested that purified enzyme is a new endonuclease and responsible for DNA degradation component of the apoptotic process. Furthermore, we study that mRNA levels of nuclear protooncogenes, c-fos, c-jun and c-myc, in FdUrd-treated cells. These results suggested that the endonuclease might be induced by the protooncogene related pathway and generates DNA fragments accompanied by cell death.

Animals↗

PubMed2000

Marked difference in tumor necrosis factor-alpha expression in warm ischemia- and cold ischemia-reperfusion of the rat liver.

Although tumor necrosis factor-alpha has been implicated in liver injury after both warm ischemia- and cold ischemia-reperfusion, it is unclear whether reactivity of the liver to these stimuli is similar with regard to cytokine expression. Here we compare the effects of warm and cold ischemia on tumor necrosis factor-alpha expression and test the hypothesis that cold ischemia preceding warm ischemia causes overexpression of this cytokine. Rat livers were flushed out with University of Wisconsin solution and subjected to varying periods of warm ischemia, cold ischemia, or cold ischemia plus warm ischemia followed by reperfusion using a blood-free perfusion model. Tumor necrosis factor-alpha and interleukin-10 release into the perfusate and bile were measured by ELISA, and expression of these cytokines and that of c-fos, c-jun, and c-myc were studied by reverse-transcriptase polymerase chain reaction. We found high levels of tumor necrosis factor-alpha in the perfusates of livers subjected to warm ischemia-reperfusion, whereas minimal or no tumor necrosis factor-alpha was detected in livers subjected to cold ischemia-reperfusion or to cold ischemia plus warm ischemia-reperfusion. Reverse-transcriptase polymerase chain reaction confirmed the above findings and showed that immediate early genes were expressed in reperfused groups of livers. Measurements of cytokine release into bile showed that neither tumor necrosis factor-alpha nor interleukin-10 were upregulated by cold ischemia-reperfusion. The results suggest that (1) warm ischemia- and cold ischemia-reperfusion of rat liver lead to very different outcomes with regard to tumor necrosis factor-alpha expression and (2) cold ischemia preceding warm ischemia prevents upregulation of tumor necrosis factor-alpha.

Animals↗

PubMed1997

Expression of the protooncogene jun is induced in the rat pancreas by cerulein infusion.

Cholecystokinin (CCK) can stimulate secretion and DNA synthesis in pancreatic acinar cells. Hyperstimulation with cerulein (a CCK analogue) induces acute edematous pancreatitis. To study the effects of in vivo pancreatic stimulation with cerulein, we analyzed the expression of the protooncogenes jun, myc, and fos on the mRNA and protein levels. RNA and protein were extracted from the pancreas of rats administered an infusion of cerulein, 10 micrograms/kg/h (Group A) or 0.25 microgram/kg/h (Group B), or saline (Group C) and sacrificed 2, 4, and 6 h after beginning the infusion and 0, 12, and 24 h and 2, 4, and 6 days after completing the infusion period. Transcript levels were studied using slot-blot analysis. Protein expression was studied using Western blot and immunohistochemistry. No changes were found for the expression of protooncogenes myc and fos on either the transcript or the protein levels. Higher jun mRNA levels were found in Group A than in Group B or C, particularly after 2 h of infusion and 12, 24, and 48 h after the end of a 12-h cerulein infusion. No significant difference was observed in Groups B and C. The jun protein behavior was similar in Groups A and B, revealing two peaks: one early during infusion and a second one after the end of a 12-h cerulein infusion. Jun protein was found mainly in the acinar cells. In conclusion, (1) acinar cells in the rat pancreas respond to cerulein stimulation by increasing the expression of jun; (2) in vivo high doses of cerulein increase the jun mRNA and jun protein levels, whereas low doses raise only the protein levels; and (3) myc and fos are apparently uninfluenced by cerulein administration.

Animals↗

PubMed1993

The in utero initiation with DMN alters the complement of cytosolic glutathione S-transferases and the phenobarbital-induced expression of c-jun and c-myc oncogenes in primary neonatal rat hepatocytes.

As revealed by a novel in utero-in vitro hepatocarcinogenesis model, a single exposure to dimethylnitrosamine (DMN) elicited in postnatal (and fetal) primary rat hepatocytes (i) immunocytochemically detectable, widespread increases in their complement of the alpha, mu and especially pi classes of cytosolic glutathione S-transferases (GSTs); and (ii) changed patterns (with respect to controls) of the phenobarbital (PB)-evoked increases in steady state levels of c-jun and c-myc mRNA's. These results indicate that DMN causes both transient cytotoxic effects and a broad, permanent initiation in fetal proliferating hepatocytes.

Animals↗

PubMed1997

S-methylcysteine and cysteine are inhibitors of induction of glutathione S-transferase placental form-positive foci during initiation and promotion phases of rat hepatocarcinogenesis.

S-Methylcysteine (SMC) occurs in a variety of plants, including Allium sativum, Phaseolus vulgaris, and Cruciferae. In this study, we synthesized five organosulfur compounds (OSCs), SMC and four analogs, and examined their modifying effects on diethylnitrosamine-induced neoplasia of the liver in male F344 rats, using the medium-term bioassay system of Ito (Ito test) based on the two-step model of hepatocarcinogenesis. In addition, we investigated the modifying effects of SMC and cysteine on the initiation stage of rat hepatocarcinogenesis. Carcinogenic potential was scored by comparing the numbers and areas of induced glutathione S-transferase placental form (GST-P)-positive hepatocellular focl. All OSCs examined had a tendency to decrease the number of GST-P-positive foci when given in the promotion stage of the Ito test, and in particular SMC and cysteine exerted significant inhibitory effects. When given during the initiation stage, these two OSCs also significantly inhibited focus formation. Regarding the mechanism underlying the inhibitory effects of SMC and cysteine, measurement of ornithine decarboxylase in SMC- and cysteine-treated liver tissues after partial hepatectomy (PH) revealed a significantly reduced activity, and the proportion of hepatocytes positive for proliferating cell nuclear antigen was significantly decreased by SMC or cysteine administration. Moreover, examination of the expression of the early response proto-oncogenes, c-fos, c-jun, and c-myc, after PH demonstrated down-regulated induction of c-jun mRNA transcripts by SMC, sustained for an eight-hour period. Our results support the view that SMC and cysteine are chemopreventive agents for rat hepatocarcinogenesis and that their intake may be importance for cancer prevention.

Animals↗

PubMed2001

Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma.

BACKGROUND: Increased expression of the proto-oncogene c-myc is a common phenomenon in hepatocellular carcinoma (HCC). The proto-oncogenes c-fos and c-jun are involved in cell cycle progression and cellular proliferation. METHODS: The objective of this study was to elucidate the mechanism of hepatocarcinogenesis with regard to the expressions of c-myc, c-fos, and c-jun. One hundred fifty biopsied HCC specimens were stained immunohistochemically for the above phenotypic markers both in tumor tissue and in adjacent nontumor tissue. RESULTS: Although the expression of c-myc was high (74%) in tumor tissue, it was significantly less compared with the expression in nontumor tissue (100%; P = 0.0002). The expression of c-myc was inversely proportional to the grade of differentiation in tumor tissue (P = 0.0108; correlation coefficient [r] = -0.244); that is, tissue with poorer histologic differentiation had a lower level of c-myc expression. There were inverse associations between the expression of c-myc and the expression of mutated p53 (P = 0.0017; r = -0.285) as well as the expression of Ki67 (P = 0.057; r = -0.147). There was significantly high expression of c-fos in tumor tissue compared with the expression in nontumor tissue (91% vs. 0%; P < 0.0001). Both the tumor tissue and the nontumor tissue had high levels of expression of c-jun (96.53% and 100%, respectively). There was a trend toward a positive association between the expression of c-fos and the expression of c-jun in tumor tissue (P = 0.07; r = 0.162). CONCLUSIONS: Because c-myc is a known inducer of wild type p53, decreased c-myc expression may lead to uncontrolled cell growth because of the lack of p53 expression that normally induces apoptosis. The coordinated expression of c-fos and c-jun in HCC may reflect the coordinated tumor cell cycle of progression and proliferation; however, future studies are required to elucidate this possibility.

Adolescent↗