[Targeted ablation of transcription factor genes].
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Animals↗
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[Concentration of proto-oncogenes in hepatocyte nuclei].
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Animals↗
Validation of northern blot analysis for quantitating the expression of several genes in rat liver.
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Actins↗
[Activity and composition of transcription factor AP-1 in rat embryonal fibroblasts transformed by oncogenes E1A plus Ha-ras].
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Adenovirus E1A Proteins↗
Induction of hepatic heme oxygenase and changes in cytochrome P-450s in response to oxidative stress produced by stilbenes and stilbene oxides in rats.
Both trans- and cis-stilbene oxide (TSO and CSO) markedly induced heme oxygenase-1 (HO-1) at the transcriptional level in rat liver. HO-1 induction by TSO and CSO was preceded by glutathione (GSH) depletion in the liver. Pretreatment of rats with buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis, enhanced GSH depletion evoked by either TSO or CSO and augmented the increase in HO-1 mRNA. In contrast, pretreatment with perfluorodecanoic acid (PFDA), which reduced hepatic GSH S-transferase activity, prevented TSO- and CSO-mediated GSH depletion and abolished HO-1 induction. In addition, TSO and CSO enhanced c-jun but not c-fos mRNA, which is in parallel with the HO-1 mRNA change. These findings indicate that the oxidative stress evoked by GSH depletion after the treatment of rats with stilbene oxides could stimulate both HO-1 and c-jun gene expression. Pretreatment with either BSO or PFDA also affected the induction of CYP2B1/2 mRNA and apoprotein by TSO or CSO, suggesting that not only the change of heme pool size but also some other unknown factor or factors may be involved in the regulation of the CYP2B1/2 and HO-1 gene expression. cis-Stilbene (CS), a parent compound of CSO, also induced HO-1 mRNA, together with hepatic GSH depletion, but trans-stilbene (TS) failed to elevate HO-1 mRNA under the experimental conditions. In addition, CS increased CYP2B1/2 mRNA, whereas TS did not. These results suggest that CS could be rapidly oxidized by cytochrome P-450 (P-450) to CSO, leading to GSH depletion in the liver. Such differences in the hepatic metabolic pathways of CS and TS are attributable to the differential effects on HO and P-450 induction by these compounds. Like other phenobarbital-type P-450 inducers, TSO and CSO also induced CYP2C6 and 3A2 apoproteins in rat liver. Stilbene oxide reduced CYP2E1 mRNA and apoproteins for CYP2E1 and 2C11. All of these findings indicate that stilbene compounds have unique effects on hepatic HO-1 and P-450 regulation in rats.
Animals↗
Human ornithine decarboxylase-overproducing NIH3T3 cells induce rapidly growing, highly vascularized tumors in nude mice.
Overexpression of human ornithine decarboxylase (ODC) under the control of strong promoters induces morphological transformation of immortalized NIH3T3 and Rat-1 fibroblasts [M. Auvinen et al., Nature (Lond.), 360: 355-358, 1992]. We demonstrate here that ODC-overproducing NIH3T3 cells are tumorigenic in nude mice, giving rise to rapidly growing, large fibrosarcomas at the site of inoculation. The tumors are capable of invading host fat and muscle tissues and are vascularized abundantly. To disclose the molecular mechanism(s) driving the tumorigenic, invasive, and angiogenic phenotype of the tumors, the ODC-overproducing cell lines and tumor tissues were analyzed for the expression of various potential regulators and mediators of cell proliferation, matrix degradation, and angiogenesis. The tumorigenicity of ODC transformants was associated with elevated polyamine levels and down-regulated growth factor receptors. The invasiveness of the ODC-induced tumors could not be attributed to overexpression of various known extracellular matrix-degrading proteases or matrix metalloproteinases. The induction of the tumor neovascularization proved not to be elicited by vascular endothelial growth factor or basic fibroblast growth factor. Instead, the ODC-overexpressing cells appeared to secrete a novel angiogenic factor(s) that was able to promote migration of bovine capillary endothelial cells in collagen gels and increase the proliferation of human endothelial cells in vitro. In parallel, ODC-transformed cells displayed down-regulation of thrombospondin-1 and -2, the negative regulators of angiogenesis. Thus, the induction of the angiogenic phenotype of the ODC transformants is likely due both to increased expression and secretion of the new angiogenesis-stimulating factor(s) and decreased production and release of the antiangiogenic thrombospondins.
3T3 Cells↗
Alpha 1 adrenergic receptor activation of proto-oncogene expression in arterial smooth muscle: regulation by nitric oxide and vascular injury.
The role of the endothelium in modulating smooth muscle cell growth is unclear. alpha 1 adrenergic receptors activate proto-oncogene expression in smooth muscle. We have now found in rat aorta that carbachol, a muscarinic cholinergic agonist that promotes release of nitric oxide (NO), inhibits expression of c-fos and c-jun mRNA induced by alpha 1 receptors. NO synthase inhibitors blocked the effects of carbachol on c-fos mRNA and a cGMP analog mimicked carbachol. After balloon injury in rat aorta using in situ hybridization, the catecholamine-induced increase in c-fos mRNA expression in the medial layer was inhibited by the alpha 1 receptor antagonists, prazosin and chloroethylclonidine. In the neointima, this response was fully blocked by prazosin; however, chloroethylclonidine only partially inhibited it. These results suggest that NO, acting through a cGMP-dependent mechanism, inhibits expression of the c-fos and c-jun genes in arteries, which may contribute to the growth-inhibiting effects of the endothelium. After endothelial damage, the activation of c-fos in neointima by adrenergic stimulation may involve a subtype of alpha 1 receptor different from that utilized in medial smooth muscle.
Animals↗
Role of interleukin (IL)-2 and IL-15 in the tumour progression of a melanoma cell line MELP, derived from an IL-2 progressor patient.
MELP is an interleukin (IL)-2 receptor (IL-2R; alpha+ beta+ gamma-) melanoma cell line that was derived, before the beginning of the immunotherapy, from a patient whose metastasis increased in size during treatment with IL-2/interferon-alpha. In these cells, continuous culture in the presence IL-2 (1000 UI/ml) causes the selection of a cell sub-line (termed MILG) expressing the gamma-chain which is tumorigenic in nude mice. Here, we further analysed the characteristics of MELP and MILG cells as well as clones selected at limiting dilution in the presence of high concentrations of IL-2 or IL-15, or those selected after transfection for the expression of a human IL-2 transgene (MELP-CL1). MELP cells, but not six other melanomas cell lines, shed two soluble immunosuppressive molecules, CD25 and intercellular adhesion molecule-1, whose levels also strongly increase in vivo during immunotherapy. In vitro MELP cells express transcripts for IL-6, transforming growth factor, basic fibroblast growth factor and vascular-endothelial growth factor. Cloning at limiting dilution was obtained in culture fed with IL-2 or IL-15. All these clones, as MILG cells, express the transcript for the IL-2R gamma chain. This could favour improved interactions with cytokines using this chain. By contrast, MELP-CL1 cells, which secrete low amounts of biologically active IL-2 (200 UI/10(6) cells) exhibit a phenotype and growth characteristics similar to those of the parental MELP cells. Indeed, a crosslinking experiment with 125I-IL-2, has showed that MELP and MELP-CL1 cells display a scant IL-2 binding ability that is strongly increased in MELP cells fed for 1 week with 1000 UI/ml IL-2. These cells, as well as MILG cells express a betagamma-complex which can also bind IL-15. IL-2 induces a rapid tyrosine phoshorylation in MILG cells, which is followed by a prolonged induction of c-fos and c-jun genes. By contrast, in MELP cells IL-2 only causes a delayed induction of c-myc gene. All MELP derivatives, but not MILG cells, express the transcripts for IL-15, which is not secreted but is present as an intracellular protein. All MELP cells express the transcript for the IL-15R alpha chain. MELP-CL1 cells are not tumorigenic in nude mice, whereas MILG cells form rapidly growing tumours in 75% of the mice. Coinjection at the same site of MILG and MELP-CL1 cells causes the rapid regression of MILG tumours in 80% of the mice, whereas their bilateral injection causes the rapid development of MILG tumours in 100% of the nude mice. Finally, treatment in nude mice of MILG cells with low amounts of IL-2 (1000 UI per mouse) and IL-15 (50 ng per mouse) induces the development of much more aggressive tumours.The expression of functional IL-2Rs in a subset of human melanomas could be responsible for tumour progression.
Adult↗
[The activation of the transcription factors of the CRE and AP-1 families correlates with the development of plasticity in Helix].
By means of gel retardation assay the DNA-binding activity of transcription factors of CRE and AP-1 families was determined in adult and juvenile (incapable for conditioning) Helix snails. The presence of DNA-binding factors of the CRE and AP-1 families was shown in adult snails. The active factors only of the CRE family were present in juveniles. Activity of these factors increased during incubation with serotonin (10(-4) M) and forscolin (5 x 10(-5) M). Both serotonin and forscolin modulate learning in adult snails. Absence of activity of AP-1 family transcription factors (the products of early fos and jun genes in juvenile snails belong to AP-1 family) may underlie the incapability for sensitization and avoidance conditioning in juvenile snails.
Aging↗
Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins.
This article reviews findings up to the end of 1997 about the inducible transcription factors (ITFs) c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif268); and the constitutive transcription factors (CTFs) CREB, CREM, ATF-2 and SRF as they pertain to gene expression in the mammalian nervous system. In the first part we consider basic facts about the expression and activity of these transcription factors: the organization of the encoding genes and their promoters, the second messenger cascades converging on their regulatory promoter sites, the control of their transcription, the binding to dimeric partners and to specific DNA sequences, their trans-activation potential, and their posttranslational modifications. In the second part we describe the expression and possible roles of these transcription factors in neural tissue: in the quiescent brain, during pre- and postnatal development, following sensory stimulation, nerve transection (axotomy), neurodegeneration and apoptosis, hypoxia-ischemia, generalized and limbic seizures, long-term potentiation and learning, drug dependence and withdrawal, and following stimulation by neurotransmitters, hormones and neurotrophins. We also describe their expression and possible roles in glial cells. Finally, we discuss the relevance of their expression for nervous system functioning under normal and patho-physiological conditions.
Activating Transcription Factor 1↗
[The expression of C-FOS, C-JUN and phosphotyrosine gene products in lung cancer].
An immunohistochemical study on C-FOS, C-JUN and phosphotyrosine (P-Tyr) cancer gene products was performed. The results showed that C-FOS had the lowest frequency of expression and P-Tyr had the highest. The positive reactions of the three cancer gene products were observed in the nucleus, nuclear membrane and cytoplasm. The expression of C-FOS in normal bronchial and alveolar tissue was 3.8% and 1.6% respectively. But in lung cancer it was 60%. The simultaneous positive expression of C-FOS and C-JUN was 56% (54 cases). Negative C-FOS and positive C-JUN was 32%. Positive C-FOS and negative C-JUN was less than 4% (4 cases). Although C-FOS and C-JUN formed a hetero-dimer by zipper structure, the C-FOS had the ability of single expression.
Adenocarcinoma↗
Expression of c-jun and Egr-1 genes in rat liver in response to partial hepatectomy, and injection of turpentine.
In rat liver stimulated by partial hepatectomy a significant expression of Egr-1 and to less extent c-jun genes was observed within 15-30 min after the surgery. The induction is transient and vanishes within one hour. Egr-1 and c-jun were also induced in liver after subcutaneous injection of turpentine, a strong inducer of acute phase response. A maximum activation of these genes was observed within 4-9 hours after administration of turpentine. Both Egr-1 and c-jun extend the list of "immediate early" genes involved in proliferative response and constitute a group of genes inducible at the beginning of acute phase response.
Acute-Phase Reaction↗
Differential expression of mitogen-activated protein kinases and immediate early genes fos and jun in thalamus in schizophrenia.
Despite a growing body of evidence demonstrating that mitogen-activated protein (MAP) kinase pathways play an important physiological role in the CNS, little is known about their role and function in various mental disorders including schizophrenia. Our previous studies have shown increased expression of several intermediates of the extracellular signal-regulated (ERK) cascade and downstream transcription targets in cerebellar vermis without any changes in mesopontine tegmentum and Brodmann's area 10 in patients with schizophrenia. Given the evidence for abnormalities in schizophrenia in a neural circuit involving the cerebellum and thalamus, the present study was conducted to examine the expression of MAP kinases extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38, as well as immediate early genes fos (c-fos and fos B) and jun (c-jun, jun B and jun D) using a Western blot analysis and reverse transcription polymerase chain reaction (RT-PCR) in postmortem thalamus from schizophrenic and control subjects. There were significant increase in ERK2, c-fos and c-jun protein and mRNA levels in thalamus of patients with schizophrenia relative to controls. No statistically significant differences were found for ERK1, Fos B, Jun B or Jun D proteins in schizophrenic and control subjects. These results taken together with our previous findings provide new evidence for selective abnormalities of distinct MAP kinases and immediate early genes c-fos and c-jun in a circuit involving the thalamus and cerebellum, which may contribute significantly to the pathophysiology of schizophrenia.
Adult↗
Selective expression of the immediate early gene c-jun in axotomized rat medial septal neurons is not related to neuronal degeneration.
In the present study, we use the anatomically well defined septohippocampal projection to study the molecular events involved in the reaction of neurons to axotomy. The expression of three immediate early genes (c-fos, c-jun, and jun B) was investigated in rat septohippocampal neurons after axotomy by bilateral fimbria-fornix transection (FFT). Moreover, the extent of retrograde degeneration in the septal complex was assessed by analyzing DNA fragmentation. In a postoperative time course analysis, a strong increase of c-jun immunoreactivity (IR) was observed in the nuclei of neurons in the medial septum/diagonal band complex (MSDB) 2 and 6 d postaxotomy, which was followed by a decline after 12 d and 3 weeks, respectively. Nine weeks after FFT, c-jun IR had disappeared. The c-jun-positive MS neurons were identified as former septohippocampal projection cells by double-labeling with the retrogradely transported tracer Fluoro-Gold injected into the hippocampus before axotomy. In line with the immunocytochemical data, there was a massive induction of c-jun mRNA in the axotomized MS neurons as visualized by in situ hybridization histochemistry. c-fos mRNA and c-fos or jun B IR were not detectable in either unoperated or lesioned medial septal neurons. Experiments using the TdT-mediated deoxyuridine triphosphate nick-end-labeling technique, designed to detect nuclear DNA fragmentation in degenerating neurons, complemented this study. During the postoperative time range studied, MS neurons did not exhibit DNA fragmentation. We conclude that MSDB neurons survive axotomy by FFT and display characteristic changes in gene expression.
Acetylcholine↗
Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2.
Cyclooxygenase-2 (COX-2) is considered to be a target for anticancer therapy. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity, but the mechanisms of action are incompletely understood. We investigated whether HDAC inhibitors blocked AP-1-mediated activation of COX-2 transcription. Trichostatin A and suberoylanilide hydroxamic acid, two structurally related inhibitors of HDAC activity, blocked AP-1-mediated induction of COX-2 expression and prostaglandin E2 biosynthesis. Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c-Jun binding to the COX-2 promoter and thereby blocked transcription. The observed reduction in binding reflected reduced levels of c-Jun. HDAC inhibitors suppressed the induction of c-jun transcription by blocking the recruitment of the preinitiation complex (RNA polymerase II and TFIIB) to the c-jun promoter. HDAC3 but not HDAC1 or HDAC2 was required for AP-1-mediated stimulation of c-jun expression. Because HDAC inhibitors suppressed the induction of c-jun gene expression, resulting in reduced COX-2 transcription, it was important to determine whether other known AP-1 target genes were also modulated. Cyclin D1 and collagenase-1 are AP-1-dependent genes that have been implicated in carcinogenesis. HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase-1 transcription by inhibiting the binding of c-Jun to the respective promoters. Taken together, these results suggest that HDAC inhibitors block the induction of c-jun transcription by inhibiting the recruitment of the preinitiation complex to the c-jun promoter. This led, in turn, to reduced expression of several activator protein-1-dependent genes (COX-2, cyclin D1, collagenase-1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors.
Blotting, Northern↗
Platelet-activating factor and polyunsaturated fatty acids in cerebral ischemia or convulsions: intracellular PAF-binding sites and activation of a fos/jun/AP-1 transcriptional signaling system.
Platelet-activating factor (PAF) is a lipid mediator formed in the early response of the central nervous system to ischemia or convulsions. Free polyunsaturated fatty acids and arachidonic and docosahexaenoic acids are accumulated along with PAF. Antagonists of PAF have been found to improve cerebral blood flow and partially block the rise in free fatty acids, an effect that may arise by way of inhibition of PAF receptors or stimulation of the reacylation of free fatty acids released upon insult. Three intracellular PAF-binding sites have been identified in rat cerebral cortex. These very high-affinity binding sites are inhibited by PAF antagonists, with certain antagonists exhibiting specificity for a particular binding site. This specificity indicates heterogeneity in these binding sites. Ischemia or stimulation also leads to protooncogene transcriptional activation. Here, we discuss studies with cells in culture showing that PAF promotes transcriptional activation of immediate-early genes. PAF activates the transcription of the immediate-early genes fos and jun, whose gene products are regulators of the transcription of other genes. Transcription of fos is also activated by convulsion or ischemia in the central nervous system. The activation of these genes by PAF can be inhibited by PAF antagonists, and is apparently accomplished by way of an AP-1 transcription regulatory sequence in the promoter region of the target genes. Studies with deletion mutants show that PAF can also exert its activating properties by way of cyclic adenosine-3',5'-monophosphate-(cAMP) and Ca(2+)-responsive elements, and suggest that PAF is involved in an interconnected network of cell signaling that may coordinate short-term and long-term responses of cells to stimulus and injury.
Animals↗
Induction of junB expression, but not c-jun, by granulocyte colony-stimulating factor or macrophage colony-stimulating factor in the proliferative response of human myeloid leukemia cells.
The proliferative effects of granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) on human hematopoietic cells have been reported, but the intranuclear mechanism of early signal response to these mitogenic stimuli remains unknown. Using an established human myeloid leukemia cell line (NKM-1) which can grow in serum-free medium in response to G-CSF or M-CSF, we examined expressions of the jun family genes, c-jun, junB, and junD, which are coexpressed by various growth factors in many tissues. In parallel with regrowth from the G0/G1 resting state by addition of recombinant human G-CSF or M-CSF after serum deprivation, NKM-1 cells showed the transient expression of the junB gene with a peak of ninefold above the basal level between 40 and 60 min. In contrast, c-jun expression was not stimulated by these CSFs. JunD expression was constitutively observed at detectable levels. Furthermore, c-fos mRNA was rapidly induced to a peak of 14-fold after CSF stimulation. Transcriptional run-on assays revealed that treatment of serum-starved NKM-1 with 50 ng/ml G-CSF or M-CSF increased the transcription rate of the junB gene and the c-fos gene by 1.8-fold and 2.9-fold, respectively, but did not induce any transcript of the c-jun gene. The results indicate that the expression of the junB and c-fos genes is activated, at least in part, at the transcriptional level in response to these CSFs. These findings suggest that the signal activating c-jun expression might not be involved in the proliferative action of G-CSF and M-CSF but junB may be one of important elements in early response events of the signal transduction system in human CSF-responsive hematopoietic cells.
Cell Division↗
The early response genes c-jun and HSP-70 are induced in regional cardiac stunning in conscious mammals.
OBJECTIVES: A reversible contractile dysfunction without necrosis after transient myocardial ischemia has been termed stunning. The molecular mechanisms underlying this phenomenon are only now beginning to be unraveled. It is conceivable that the expression of early-response genes may play a crucial role in stunning. METHODS: The expression of HSP-70, c-jun, and GRP-94 was investigated in a chronically instrumented dog model (n = 9). The left anterior descending coronary artery was occluded temporarily for 10 minutes after the animals had fully recovered from instrumentation. The wall thickening fraction was measured in the left anterior descending coronary artery and the nonischemic ramus circumflex of the left coronary artery-perfused region. When the wall thickening fraction of the left anterior descending coronary artery had recovered to 50% of preocclusion values, tissue samples were obtained from the areas perfused by the left anterior descending coronary artery and the nonischemic ramus circumflex of the left coronary artery. RESULTS: The messenger RNA of HSP-70 was increased to 214% +/- 26% in the area perfused by the left anterior descending artery compared with that perfused by the nonischemic ramus circumflex of the left coronary artery. There was no difference in the messenger RNA of GRP-94. The HSP-70 content was elevated to 130% +/- 14% in the left anterior descending artery compared with the area perfused by the ramus circumflex of the left coronary artery, and the c-jun protein content was 70% +/- 25% higher in the ischemic area compared with the control area. CONCLUSIONS: The induction of early-response genes observed here may indicate that they play an adaptive role in myocardial stunning, even in conscious mammals.
Animals↗