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PubMed1991

Expression of c-jun, jun B and jun D proto-oncogenes in human peripheral-blood granulocytes.

We have found that purified human peripheral-blood granulocytes express constitutively significant levels of proto-oncogenes c-jun, jun B and jun D mRNA. Upon functional activation of granulocytes by 4 beta-phorbol 12-myristate 13-acetate (PMA), the levels of c-jun, jun B and jun D transcripts were increased. The three jun genes showed a similar time course in their induction by PMA, maximal mRNA levels being reached after 60 min of induction. These results suggest that expression of c-jun, jun B and jun D genes might be involved in terminal granulocyte differentiation or in regulating granulocyte functionality.

Blotting, Northern↗
PubMed1993

Evidence for enhanced expression of c-fos, c-jun, and the Ca(2+)-activated neutral protease in rat liver following carbon tetrachloride administration.

The effects of CCl4 on hepatic c-fos and c-jun gene expression were examined, and the correspondence between intermediate-early gene expression and the expression of the Ca(2+)-activated neutral proteinase (mu and mCANP) characterized. Administration of CCl4 to rats resulted in a pronounced dose- and time-dependent increase in c-jun and c-fos mRNA levels (approximately 8 to 17-fold) as detected by either Northern blot or RT-PCR analyses. The expression of mu and mCANP following CCl4 treatment was monitored by Northern blot analysis and mu and mCANP mRNA levels were found to be elevated approximately 5- to 15-fold over the time period of 18 to 24 h. Experiments were performed to determine whether the Fos-Jun heterodimeric AP-1 transcription factor complex bound the AP-1-like binding motif present in the mCANP gene. Gel retardation assays using hepatic nuclear extracts from CCl4-treated animals revealed binding of a protein to the AP-1-like motif present in the mCANP gene and competition and supershift assays confirmed the specificity of AP-1 transcription factor binding. These results show that CANP gene expression is enhanced in response to oxidative cellular damage and that the AP-1 complex may be involved in the regulation of CANP gene expression.

Animals↗
PubMed1992

Vanadate-induced gene expression in mouse C127 cells: roles of oxygen derived active species.

An underinvestigated aspect of the mitogenic and cell regulatory actions of vanadium is the regulation of gene expression. Among the fifteen cellular genes studied in cultured mouse C127 cells, vanadium (as 10 microM sodium vanadate) increased levels of mRNA of the actin and c-Ha-ras to four times control values. These increases represented de novo synthesis of mRNA, since they were inhibited by actinomycin D. Vanadate did not increase mRNA corresponding to c-src, c-mos, c-myc, p53, HSP70, pODC or RB genes, and expression of c-erb A, c-erb B, c-sis and c-fes genes was undetectable whether vanadium was present or not. Expression of a third gene affected by vanadium, c-jun, was augmented by addition of a reductant or oxidant together with the vanadate. Addition of NADH (marginally effective on its own) or H2O2 (effective alone) dramatically enhanced the effect of vanadate on c-jun gene expression. Catalase inhibited the effect of NADH partly. The vanadate-stimulated expression of actin and c-Ha-ras mRNA were unaffected by oxidants, reductants, metal chelators, or anti-oxidant enzymes. Evidently vanadate acts by two separate mechanisms on these two categories of genes. The alternate hypothesis that the actions of vanadate on actin and c-Ha-ras were mediated by a protein kinase cascade was inconsistent with the following observations. Neither insulin nor epidermal growth factor increased mRNA levels of c-Ha-ras or actin gene. Neither genistein (a tyrosine kinase inhibitor) nor pretreatment with 12-O-tetradecanoylphorbol-13-acetate blocked the actions of vanadate on these genes. Clearly the biological actions of vanadium depend in part on altered expression of genes. Since two of the genes are proto-oncogenes, this mechanism is potentially relevant to the mitogenic responses of cells to vanadium.

Animals↗
PubMed1989

Molecular analysis of chromosome 1 abnormalities in neuroblastoma.

Tumor cells from 70% of neuroblastoma patients contain a deletion of part of the short arm of chromosome 1, indicating that this chromosomal region includes a gene involved in tumor formation. To more precisely evaluate the boundaries and mechanisms involved in generating these deletions, we have examined four neuroblastoma cell lines using a combination of somatic cell hybridization, isozyme analysis, and nucleic acid hybridization employing both standard and restriction fragment length polymorphic probes. The data suggest that the truncation of chromosome 1 in these neuroblastomas was most likely due to a complex translocation and deletion mechanism rather than a simple unbalanced translocation or terminal or interstitial deletion. This conclusion is supported by the frequent removal of MYCL from the altered chromosome 1 to another chromosome. Furthermore, the data suggest that the frequency of breakpoints previously assigned by karyotypic analysis to bands other than 1p32 in neuroblastomas may be overestimated. Finally, this study identified a breakpoint at 1p32 that was localized between the genes JUN and MYCL for one neuroblastoma thus establishing the order of these genes as centromere, JUN, MYCL, telomere. We conclude that the observed breakpoints within chromosome 1p in human neuroblastoma are not as variable as previously described and suggest the results of this study provide evidence for the involvement of specific DNA sequences within 1p32 in the generation of neuroblastoma.

Animals↗
PubMed2005

Pre-mRNA processing enhancer (PPE) elements from intronless genes play additional roles in mRNA biogenesis than do ones from intron-containing genes.

Most mRNA-encoding genes require introns for efficient expression in high eukaryotes. However, mRNAs can efficiently accumulate in the cytoplasm without intron excision if they contain cis-acting elements such as the post-transcriptional regulatory element (PRE) of hepatitis B virus (HBV), the constitutive transport element (CTE) of Mason-Pfizer monkey virus (MPMV), or the pre-mRNA processing enhancer (PPE) of herpes simplex virus' thymidine kinase (HSV-TK) gene. We compared the activities of these viral elements, the Rev-responsive element (RRE) of the human immunodeficiency virus (HIV), and the human c-Jun gene's enhancer (CJE), an element newly identified here, to enable expression of an intronless variant of the human beta-globin gene. The PRE, PPE and CJE from naturally intronless genes, but not the CTE or RRE from intron-containing genes, significantly enhanced stability, 3' end processing and cytoplasmic accumulation. When the transcripts included the beta-globin gene's first intron, the PRE, PPE and CJE still enhanced mRNA biogenesis, in some cases without intron excision. Thus, elements enabling stability, 3' end formation and nucleocytoplasmic export, not the presence of introns or their excision per se, are necessary for mRNA biogenesis. While the CTE and RRE primarily enhance nucleocytoplasmic export, PPE-like elements from naturally intronless genes facilitate polyadenylation as well.

Active Transport, Cell Nucleus↗
PubMed1994

Butyrate synchronization of hepatocytes: modulation of cycling and cell cycle regulated gene expression.

To develop a model for studies of liver growth control, we characterized cell cycle synchronization of liver-derived cells with sodium butyrate. Exposure of cultured HTC (rat hepatoma) cells to 5 mM butyrate arrested cell growth in a reversible manner. Flow cytometric analysis revealed that butyrate-treated HTC cells were restricted in G0/G1, as well as S/G2M phases. After release from butyrate arrest, HTC cells underwent synchronous cycles of DNA synthesis and transited through S phase. Inhibition of cell growth by butyrate was associated with a complex pattern of cell cycle regulated gene expression, including a decoupling of c-fos and c-jun gene expression. Transcription of c-fos, as well as c-jun increased with butyrate arrest, whereas steady rate mRNA levels of c-jun only were increased, suggesting additional regulation of c-fos. In addition, butyrate-arrested cells exhibited a transcriptionally determined accumulation of H3 histone, C-Ha-ras and ornithine decarboxylase mRNAs, suggesting that cell cycle-related check points following the onset of S phase were modulated. An increase in c-myc mRNA levels in butyrate-arrested cells was post-transcriptionally regulated. After release from butyrate-arrest, the abundance of immediate early, as well as S phase regulated, gene expression changed coordinately with S phase cell transitions. Thus, exposure of HTC cells to butyrate modulates cell cycle regulated gene expression, inhibits cycling, and results in accumulation of cells in specific compartments. Synchronization of liver cells with butyrate should, therefore, provide a useful model for defining cell cycle-related events in response to various mitogenic stimuli.

Animals↗
PubMed1992

Transformation by Jun: requirement for leucine zipper, basic region and transactivation domain and enhancement by Fos.

Mutants in the leucine zipper and basic regions of mouse c-jun were tested for transformation in chicken embryo fibroblast cultures. Reduction or elimination of the ability of Jun to dimerize or to bind to DNA severely decreased transformation. A chicken v-jun gene from which the major transactivation domain was deleted also failed to transform. We conclude that an intact leucine zipper, basic region and transactivation domain are required for Jun-induced oncogenic transformation. Coexpression of chicken c-Fos increased formation of transformed foci by Jun proteins of moderate to low oncogenic potency but had no effect on highly transforming Jun. Chicken c-Fos could also transform chicken embryo fibroblasts on its own, albeit after prolonged culture and at a low efficiency.

Amino Acid Sequence↗
PubMed1994

Prolonged expression of c-jun and associated activity of the transcription factor AP-1, during apoptosis in a human leukaemic cell line.

The product of the c-jun gene is a component of the transcription factor AP-1, which plays a critical regulatory role in the cellular response to certain proliferative stimuli. In this report, we demonstrate the prolonged expression of c-jun mRNA during apoptosis induced in a human leukaemic T-cell line, CEM C7, by treatment with either dexamethasone or gamma-radiation. However, overexpression of the c-jun mRNA was not accompanied by either increased expression of jun protein, or increased AP-1 DNA binding activity. Indeed, a decrease in AP-1 DNA binding activity was seen in response to both inducing stimuli. This decrease in AP-1 binding activity may be mediated by an increase in the activity of an AP-1 inhibitory factor, as the steady state levels of jun protein remained constant during the onset of apoptosis, and cytosolic AP-1 inhibitory activity was found to increase, concomitant with the decrease in AP-1 DNA binding activity. Our data demonstrate the complexity of the mechanisms involved in the regulation of c-jun expression during the onset of apoptosis, and suggest a novel mode for the regulation of AP-1 activity during the cessation of proliferation.

Apoptosis↗
PubMed1996

DNA repair domains within a human gene: selective repair of sequences near the transcription initiation site.

We describe a new form of DNA repair heterogeneity along the genome. The repair rate of UV-induced cyclobutane pyrimidine dimers (CPDs) was measured at single nucleotide resolution along the promoter and transcribed sequences of the human JUN gene in UV-irradiated diploid fibroblasts. The promoter of this gene contains an array of sequence-specific transcription factors located between nucleotides -200 and -50 relative to the major transcription start site. These sequences are repaired slowly; at many sites >50% of the CPDs are left unrepaired after 24 h. However, repair rates are 10-fold faster near the transcription initiation site. This very fast repair is seen on both DNA strands between nucleotides -40 and +100 where at most positions >90% of the dimers are repaired within 4 h. There is a general gradient of repair efficiency of the transcribed DNA strand with faster repair within the 5'-end and diminished repair towards the 3'-end of the gene. The fast repair rates seen near the transcription initiation site may be explained by increased local concentrations of DNA repair factors that are associated with general transcription factors (e.g. TFIIH) functioning in transcription initiation. This domain-specific DNA repair may aid in maintaining transcription initiation of essential genes after DNA damage.

Base Sequence↗
PubMed1995

The possible role of a central nervous system dopaminergic mechanism in hepatic c-fos protein expression following peritoneal sepsis.

OBJECTIVE: To investigate the hypothesis that a central dopaminergic mechanism may regulate hepatic c-fos and c-jun gene expression following peritoneal sepsis. METHODS: First, dopamine or vehicle was instilled into a stereotaxically placed intracerebral-ventricular (ICV) cannula with or without D1 (SCH 23390) or D2 (haloperidol) antagonist pretreatment in a rat model, and the effect on hepatic c-fos or c-jun protein expression was investigated. Second, we investigated the effect of haloperidol and vehicle treatment following cecal ligation and puncture (CLP)-induced sepsis with respect to hepatic c-fos protein expression, c-jun protein expression, and survival. RESULTS: Intracerebral-ventricular dopamine treatment increased hepatic c-fos immunoreactive protein but had no effect on hepatic c-jun immunoreactive protein expression. Pretreatment with SCH 23390 inhibited ICV dopamine treatment-induced hepatic c-fos immunoreactive protein expression. Haloperidol pretreatment synergized with ICV dopamine treatment to overexpress hepatic c-fos protein. Haloperidol treatment significantly increased CLP-induced hepatic c-fos and c-jun protein expression and improved survival following CLP. CONCLUSIONS: Hepatic c-fos protein expression may be regulated, in part, by a central nervous system-mediated dopaminergic D1 receptor mechanism. Treatment with the D2 receptor antagonist, haloperidol, increases sepsis-induced hepatic c-fos and c-jun protein expression and improves survival following peritoneal contamination.

Animals↗
PubMed1996

Jun: transcription factor and oncoprotein.

Since the discovery of v-jun as the transforming protein of the sarcoma virus 17 three mammalian homologues of v-jun have been isolated. All three jun genes respond to a multitude of agents, and the encoded proteins in turn bind to and regulate, positively or negatively, the transcription of dependent genes, thereby influencing cellular fate. In addition, through transcription factor "cross-talk" Jun influences the transcription of genes regulated by different classes of transcription factors, such as steroid hormone receptors. Although the role of Jun proteins in transcriptional regulation has been thoroughly analyzed in recent years, the role of Jun proteins in oncogenesis is still poorly understood.

Binding Sites↗
PubMed1995

c-jun expression and growth stimulation in human ovarian carcinoma cell lines following exposure to cytokines.

We evaluated the effects of recombinant human G-CSF, rhGM-CSF, rhM-CSF and rhIL-1 alpha on proliferation and regulation of c-jun gene expression in 4 human ovarian-carcinoma (HOC) cell lines, NIH:OVCAR-3, SK-OV-3, HEY and BG-1, and in one primary ovarian tumor in vitro. The cytokines were administered in concentrations of 0.1 U/ml to 1000 U/ml. Cell growth was measured by crystal-violet- and thiazolyl-blue(MTT)-based cell counts. c-jun transcripts were measured by the solution hybridization/RNAse protection assay. RhM-CSF and rhGM-CSF showed no growth stimulation of any of the 5 cell lines tested. Results from exposure to rhG-CSF were different. The cell lines NIH:OVCAR-3, SK-OV-3, BG-1 and the primary ovarian tumor showed no proliferative response. A 2- to 3-fold increase in proliferation was observed in the HEY HOC cell line. rhIL-1 alpha led to growth stimulation in the BG-1 cell line, but showed an inhibitory effect in the NIH:OVCAR-3 cells. No effects of rhIL-1 alpha were observed in the remaining 2 cell lines nor in the primary ovarian tumor. Growth stimulation was accompanied by an increase in c-jun expression in the HEY cell line, and the BG-1 cell line. No alterations in c-jun expression were observed in the remaining 3 cell lines. Our results indicate that rhG-CSF or rhIL-1 alpha influence cell proliferation in 2 out of 5 human ovarian-tumor cell lines, accompanied by an increase in c-jun expression.

Cell Division↗
PubMed1992

cis-Diamminedichloroplatinum(II) induces c-jun expression in human myeloid leukemia cells: potential involvement of a protein kinase C-dependent signaling pathway.

cis-Diamminedichloroplatinum(II) (CDDP) is a chemotherapeutic agent known to inhibit DNA, RNA, and protein synthesis. The cytotoxicity of this drug is thought to result from the formation of DNA intrastrand cross-links. The present work demonstrates that treatment of human myeloid leukemia cells (HL-60, U-937, and KG-1) with CDDP is associated with increased expression of the c-jun gene and that this effect is related to activation by a transcriptional mechanism. The results also demonstrate that treatment with CDDP is associated with increases in protein kinase C (PKC) activity. Furthermore, the finding that pretreatment with H7, an inhibitor of PKC, abrogates the effect of CDDP on c-jun expression suggested the involvement of PKC in this process. Down-regulation of PKC by prolonged pretreatment with 12-O-tetradecanoylphorbol-13-acetate was also associated with inhibition of CDDP-induced c-jun expression. The results further demonstrate that there is a temporal relationship between the CDDP-induced increase in c-jun expression and the occurrence of internucleosomal DNA cleavage characteristic of programmed cell death. These findings suggest that c-jun may be involved in the cellular response to DNA-damaging agents, such as CDDP, and that this effect may be mediated by a PKC-dependent pathway.

Actins↗
PubMed1993

c-jun expression in substantia nigra neurons following striatal 6-hydroxydopamine lesions in the rat.

The proto-oncogene c-jun is thought to play a role in the control of growth and differentiation of many cell types. It has been demonstrated previously that damage to axons of peripheral motor or sensory neurons resulted within 24 h in substantially increased levels of the c-jun gene in the parent cell bodies. These increased levels of c-jun protein and messenger RNA are maintained if the damaged nerve is ligated, but return to basal levels if the peripheral nerve is allowed to regenerate. We have examined the expression of immediate early genes in central neurons of the rat and now show that a 6-hydroxydopamine-induced axotomy of the dopaminergic nigrostriatal pathway results in a substantial increase in the levels of c-jun (but not c-fos) messenger RNA and protein within neurons of the substantia nigra pars compacta. However, the central neuronal response differs from the peripheral nerve response in that it becomes maximal at four to eight days post-lesion and is transient, declining to control levels in nigral neurons by 14 days post-lesion. These expression patterns may be related to the differential capacity of central and peripheral neurons to regenerate. The precise role of c-jun in these processes, or in the regenerative response, is unclear but it remains possible that c-jun activation following axon damage leads to an increased expression of genes which are essential for the regenerative response. The nature of the mechanism by which c-jun levels are attenuated in central neurons is also unclear, but inhibitory factors, generated by the central environment, may play a role.

Animals↗
PubMed1996

Expression of c-fos, jun D and pp60c-src+ mRNAs in the developing and grafted rat striatum.

Expression of the mRNAs of the proto-oncogenes pp60c-src+, c-fos and jun D were studied using in-situ hybridisation histochemistry in the developing striatum and in striatal grafts. The temporal patterns of mRNA expression were monitored in the striatum of the normal developing rat from the 12th day of gestation (E12) to 10 days postnatally, and were compared to the changes in gene expression observed in E13-E14 primordial striatal tissue grafts 7, 15 and 30 days after implantation in the ibotenic acid-lesioned striatum of adult rats. During development, all three proto-oncogenes were most highly expressed just before birth, at E19. Striatal expression of all three proto-oncogenes was markedly reduced after birth and remained at a low level through to adulthood. A different mode of expression was observed in the transplanted striatum which was unique to each particular gene. jun D and pp60c-src+ were expressed for a longer time period in the grafted primordial cells than in normal development, whereas no c-fos expression could be detected in the grafts. These results suggest that transplantation of embryonic neural cells into the host brain may affect the normal developmental regulation of such cells and their expression of some proto-oncogenes.

Animals↗
PubMed2004

[PI 3-kinase activity is necessary for F9 mouse embryonic carcinoma cell proliferation].

Embryonic carcinoma (EC) cells and embryonic stem (ES) cells have short cell cycles and, accordingly, proliferate very fast. Serum starvation does not suppress proliferation of EC and ES cells that allows to assume independence of their proliferation from the activity of cascades induced by serum. In the present work, we used flow cytometry to investigate how specific MAP-kinase and PI3-kinase inhibitors may influence proliferation and cell cycle of EC F9 cells. It is established that inhibitors of ERK-, JNK- and p38-kinases do not suppress EC F9 cell proliferation. It is possible to assume that proliferation of EC cells is supported by constitutive activity of down-stream cell cycle regulators, for example, E2F1 transcription factor. Since PI3-kinase inhibitor LY294002 causes reduction of S-phase and accumulation of G1-phase F9 cells, PI3-kinase mediated cascades seem to be constantly activated and involved in phosphorylation of important cell cycle regulators. The analysis of transcription of immediate-early genes in undifferentiated cells has shown that c-fos and c-jun genes are strongly activated by serum, and that ERK-kinase plays the main role in activation of c-fos transcription, while activation of c-jun transcription depends predominantly on p38-kinase. It is necessary to note that PI3-kinase inhibitor increases effect of serum stimulation of c-fos promoter. It means that the PI3-kinase dependent cascade negatively influences the cascade, which activates c-fos transcription. Thus, the transcription of c-fos and c-jun is not connected with of EC F9 cell proliferation. The proliferation of these cells depends on PI3-kinase activity.

Animals↗
PubMed1993

Differential induction of c-jun expression by PGF2-alpha in rat ovary, uterus and adrenal.

The influence of PGF2 alpha on c-jun gene expression in ovary, uterus and adrenal was examined. Three and seven day postovulatory PMSG primed immature rats received 500 ug PGF2 alpha by two subcutaneous injections 8 hours apart. Control rats received saline. Animals were sacrificed 30 minutes after the second injection of PGF2 alpha. Tissues were obtained and frozen in liquid nitrogen. RNA extracted from ovary, uterus and adrenal was analyzed by Northern and slot blot. c-jun was expressed differentially in these organs. An increase in c-jun expression by PGF2 alpha treatment occurred in the ovary but not in the adrenal and uterus. The effect of PGF2 alpha on c-jun was stronger in older compared to younger corpora lutea. These results indicate differential regulation of c-jun by PGF2 alpha in steroidogenic and steroid responsive tissues and that c-jun might be linked to the mode of action of PGF2 alpha in luteolysis.

Adrenal Glands↗
PubMed1995

Bombesin stimulates c-fos and c-jun mRNAs in small cell lung cancer cells.

The effects of bombesin/gastrin-releasing peptide (BN/GRP) on c-fos and c-jun gene expression were investigated using small cell lung cancer (SCLC) cells. BN (10 nM) increased c-fos mRNA fivefold using NCI-H345 or NCI-H510 cells. The increase was concentration dependent with 1 nM BN half-maximally increasing c-fos mRNA. Also, the increase in c-fos mRNA caused by BN was time dependent, being maximal after 1 h and returning to basal values after 4 h. GRP and GRP(14-27) but not GRP(1-16) increased c-fos mRNA. BW2258U89 (1 microM), a GRP receptor antagonist, had no effect on basal c-fos but inhibited the increase in c-fos mRNA caused by 10 nM BN. Also, BN transiently increased c-jun mRNA twofold and the increase caused by BN was blocked by BW2258U89. These data suggest that GRP receptors may regulate nuclear oncogene gene expression in SCLC cells.

Bombesin↗