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At least 19 recordsLinked to original sources
PubMed1996

The human cytomegalovirus major immediate-early gene.

Immediate-early genes function to regulate viral and cellular gene expression during the course of virus replication. The major immediate-early gene region of human cytomegalovirus plays a key role in affecting activation and repression of viral and cellular genes. These proteins intimately associate and/or interact with viral and cellular proteins during this process. Herein, we will discuss the current understanding of this complex gene region.

Antigens, Viral↗
PubMed2001

Examination of the involvement of protein kinase A in D2 dopamine receptor antagonist-induced immediate early gene expression.

Immediate early genes (IEGs) are induced by different signaling pathways. It has been proposed that D2 dopamine receptor blockade induces IEG expression through activation of protein kinase A (PKA), although few studies have examined this issue in vivo. We infused the PKA inhibitor H-89 into the striatum of male rats, followed 30 min later by systemic administration of eticlopride. Eticlopride-induced c-fos and zif268 mRNA expression in striatum was not blocked by H-89. In addition, eticlopride did not produce measurable levels of PKA activity in striatum, whereas the cAMP activator Sp-8-Br-cAMPs increased levels of activated PKA. Neither the adenosine A2a receptor agonist CGS 21680 nor the phosphodiesterase-4 inhibitor rolipram, each of which should increase PKA activation, potentiated eticlopride-induced IEG expression. To test whether other signaling pathways are involved in eticlopride-mediated gene induction, we also infused inhibitors of the mitogen-activated and calcium/calmodulin-dependent protein kinases into animals and then treated them with eticlopride. The data suggest that eticlopride-induced IEG expression is not solely dependent on these kinases either. These data suggest that PKA activation may not be necessary for induction of IEGs by D2 dopamine receptor antagonists and that other intracellular signaling pathways may be involved.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

The expression of immediate early gene X-1 (IEX-1) is differentially induced by retinoic acids in NB4 and KG1 cells: possible implication in the distinct phenotype of retinoic acid-responsive and -resistant leukemic cells.

In a cell-type- and stimulus-dependent fashion, the early response gene immediate early gene X-1 (IEX-1) is involved in growth control and modulation of apoptosis. The present study demonstrates that, in the two acute promyelocytic leukemia (APL) cell lines NB4 and KG1, exhibiting distinct responsiveness to retinoic acids (RAs), IEX-1 expression is rapidly (30-60 min) induced by all-trans- or cis-RA and independently of other signal transduction mediators, such as TNFalpha, NF-kappaB or MAP kinases. In NB4 cells (expressing PML-RARalpha), this increase is transient and completely reversible, along with a cell cycle arrest, ongoing differentiation and lower sensitivity to anti-cancer-drug-induced apoptosis. In contrast, the RA-induced IEX-1 expression in KG1 cells (expressing PLZF-RARalpha) persists over days, along with continued cell cycle progression and increased apoptotic sensitivity. Furthermore, two functional RA-response elements in the IEX-1 promoter were identified by gel shift and luciferase reporter gene assays. IEX-1 might be a rather unique transcriptional target of the two X-RARalpha fusion receptors exhibiting distinct responsiveness to RAs. Following a different time course of direct transcriptional induction by PML-RARalpha and PLZF-RARalpha in NB4 and KG1 cells, respectively, IEX-1 expression may be involved in the modified actions of these receptors and the distinct phenotypes of APL cells.

Antineoplastic Agents↗
PubMed1999

The interleukin-1 type 2 receptor gene displays immediate early gene responsiveness in glucocorticoid-stimulated human epidermal keratinocytes.

Human epidermal keratinocytes (HEKs) in primary culture (P2-P4) were used to study glucocorticoid (GC)-mediated transcription of the genes encoding the constitutively expressed interleukin-1 type 1 receptor (IL-1R1) and the inducible interleukin-1 type 2 receptor (IL-1R2). Utilizing Northern dot blot analysis and a quantitative reverse transcription-polymerase chain reaction protocol for IL-1R1 and IL-1R2, dexamethasone and, in particular, the budesonide epimer R were shown to effectively and rapidly induce transcription from the IL-IR2 gene when compared with IL-1R1 or beta-actin RNA message levels in the same sample. Southern blot analysis of newly generated IL-1R2 reverse transcription-polymerase chain reaction products using end-labeled IL-1R2 intron probes suggested that GC enhancement of IL-1R2 expression was regulated primarily at the level of de novo transcription. GC-induced IL-1R2 gene transcription displayed features characteristic of a classical immediate early gene response, including a signal transduction function, a relatively low basal abundance, a rapid, transient induction, cycloheximide superinduction, actinomycin D suppression, and a rapid decay of IL-1R2 RNA message. Parallel time course kinetic analysis of IL-1R2 RNA message levels with Western immunoblotting revealed tight coupling of de novo IL-IR2 gene transcription with translation of the IL-1R2 RNA message; a newly synthesized ( approximately 46-kDa) IL-1R2 protein was detected in the HEK growth medium as early as 1 h after budesonide epimer R treatment. These data indicate that different GC compounds can variably up-regulate the IL-1R2 response in HEKs through transcription-mediated mechanisms and, for the first time, suggest that a gene encoding a soluble cytokine receptor can respond like an immediate early gene.

Budesonide↗
PubMed1999

Immediate early gene expression in dog thyrocytes in response to growth, proliferation, and differentiation stimuli.

In dog thyroid cells, insulin or IGF-1 induces cell growth and is required for the mitogenic action of TSH through cyclic AMP, of EGF, and of phorbol esters. HGF per se stimulates cell proliferation and is thus the only full mitogenic agent. TSH and cAMP enhance, whereas EGF phorbol esters and HGF repress differentiation expression. In this study, we have investigated for each factor and regulatory cascade of the intermediate step of immediate early gene induction, that is, c-myc, c-jun, jun D, jun B, c-fos, fos B, fra-1, fra-2, and egr1; fra-1 and fra-2 expressions were very low. TSH or forskolin increased the levels of c-myc, jun B, jun D, c-fos, and fos B while decreasing those of c-jun and egr1. Phorbol myristate ester stimulated the expression of all the genes. EGF and HGF stimulated the expression of all the genes except jun D and for EGF fos B. All these effects were obtained in the presence and in the absence of insulin, which shows that insulin is not necessary for the effects of the mitogens on immediate early gene expression. The definition of the repertoire of early immediate genes inductible by the various growth cascades provides a framework for the analysis of gene expression in tumors. (1) Insulin was able to induce all the protooncogenes investigated except fos B. This suggests that fos B could be the factor missing for insulin to induce mitogenesis. (2) No characteristic pattern of immediate early gene expression has been observed for insulin, which induces cell hypertrophy and is permissive for the action of the other growth factors. These effects are therefore not accounted for by a specific immediate early gene expression. On the other hand, insulin clearly enhances the effects of TSH, phorbol ester, and EGF on c-myc, junB, and c-fos expression. This suggests that the effect of insulin on mitogenesis might result from quantitative differences in the transcription complexes formed. (3) c-myc, c-fos, and jun B mRNA induction by all stimulating agents, whether inducing cell hypertrophy, or growth and dedifferentiation, or growth and differentiation, suggests that, although these expressions are not sufficient, they may be necessary for the various growth responses of thyroid cells. (4) The inhibition of c-jun and egr1 mRNA expression, and the marked induction of jun D mRNA appear to be specific features of the TSH cAMP pathway. They might be related to its differentiating action. (5) fos B, which is induced by TSH, forskolin, phorbol ester, and HGF but not by insulin, could be involved in the mitogenic action of the former factors.

Animals↗
PubMed1989

DNA sequence and comparative analyses of the equine herpesvirus type 1 immediate early gene.

The immediate early (IE) proteins of herpesviruses are important regulatory factors which control the expression of genes at the transcriptional level. We report the DNA sequence of the immediate early gene of the alphaherpesvirus equine herpesvirus type 1 (EHV-1). This sequence is shown to be extremely rich in guanine and cytosine, resulting in a highly biased codon usage. The IE gene region possesses 38 open reading frames (ORFs) greater than 300 bp in length, 11 of which have coding regions of at least 100 amino acids (aa) following potential translation initiator codons. The largest ORF consists of 1487 codons (4461 bp) starting with the first ATG and would encode a protein of MW 155,000. TATA and CCAAT sequences as well as several potential cis-acting elements lie upstream to the major ORF. The deduced amino acid sequence for the 155,000 protein has a high degree of homology to the herpes simplex virus type 1 (HSV-1) ICP4 protein and its varicella-zoster virus (VZV) homolog. The regions of the EHV-1 IE protein that are homologous with these proteins correspond to the previously determined pattern of homology between the HSV and VZV IE polypeptides. However, there are are a number of differences within these broadly defined regions. It is therefore expected that this comparative study will facilitate the identification of functionally important residues within the amino acid sequence of IE proteins.

Amino Acid Sequence↗
PubMed2005

Identification and characterization of herpesviral immediate-early genes.

Immediate-early (IE) genes are the first class of viral genes expressed after primary infection or reactivation. As transcription of IE genes does not require prior viral protein synthesis, this class of genes is experimentally defined by their transcription following primary infection or reactivation in the presence of inhibitors of protein synthesis. This chapter describes an approach to identify IE genes in a novel herpesvirus genome. Transcription of IE genes is selectively induced with sodium butyrate in the presence of the protein synthesis inhibitor cycloheximide. The transcripts of the induced genes are identified by using a cDNA subtraction-based method of gene expression screening.

Blotting, Northern↗
PubMed2005

Mapping behaviorally relevant neural circuits with immediate-early gene expression.

Immediate-early genes have gained widespread popularity as activity markers for mapping neuronal circuits involved in specific behaviors in many different species. In situ immediate early gene detection methods provide cellular level resolution, a major benefit for mapping neuronal networks. Recent advances using fluorescence in situ hybridization also afford temporal resolution, enabling within-animal activity maps for two distinct behaviors. Moreover, use of transgenic mice with fluorescent reporter proteins driven by immediate early gene promoters is enabling repeated measurements, over long time scales, of cortical activity within the same animal. These methodological innovations, coupled with recent advances in fluorescence imaging and probe development, will enable large scale mapping of behaviorally relevant circuits with temporal and three-dimensional spatial resolution in experimental animals.

Animals↗
PubMed1998

Evolutionary conservation of the immediate-early gene ZENK.

Immediate-early genes are part of a cellular response mechanism that reacts to biochemical, electrical, pharmacological, and physiological stimuli as well as changes in behavioral state. In the brain, immediate-early genes-such as egr-1 have been used as markers for neuronal activity. These markers could be invaluable in studies that utilize the chick-quail chimaera system to investigate neural components of behavior. Therefore, we decided to clone avian homologs of immediate-early genes to allow an expression analysis in behavioral paradigms and to determine the degree of conservation among diverse species. We report in this study the cloning of the ZENK gene, an egr-1 homolog, from chicken, quail, zebrafinch, and canary. We show that the coding region of this gene is highly conserved and follows established phylogenetic relationships. In situ hybridization demonstrates that the expression pattern is also conserved among species. We further demonstrate that there are regions in the 3' untranslated area of the ZENK gene that are as highly conserved as the protein-coding region and that may play a role in postranscriptional regulatory mechanisms of ZENK gene expression.

Amino Acid Sequence↗
PubMed1992

Calcium regulation of immediate early gene transcription.

Cellular immediate early genes (IEGs) are a class of genes whose transcription is transiently activated within minutes of exposure of cells to a wide range of extracellular stimuli. In mature neurons IEG expression can be triggered by a variety of neutrotransmitters and neurotrophic factors. The IEGs, many of which encode transcription factors, are believed to control the physiological response of the cells to the initial stimulation event by activating secondary programs of gene expression. The mechanism by which membrane depolarization/Ca2+ influx trigger the activation of one IEG, c-fos, has been characterized in PC12 cells. In these cells, the cAMP response element-binding protein (CREB) functions as a Ca2+ regulated transcription factor. In addition, CREB is an in vitro substrate for several Ca2+ calmodulin-dependent protein kinases (CaM kinases). These results suggest a model whereby activation of voltage sensitive Ca2+ channels stimulates CaM kinase activation leading to CREB phosphorylation and c-fos transcriptional activation.

Animals↗
PubMed1993

Only the HLA class I gene minimal promoter elements are required for transactivation by human cytomegalovirus immediate early genes.

The immediate early (IE) genes of human cytomegalovirus (HCMV) are expressed in lymphocytes and are known to transactivate both viral and cellular promoters. The mechanism by which IE gene products of HCMV transactivate expression of the HLA A2 gene promoter in Jurkat cells, a T-lymphocyte cell line, was investigated. Transient expression assays were performed using plasmids containing the HLA A2 promoter-regulatory region linked to the bacterial chloramphenicol acetyltransferase (CAT) gene and a plasmid expressing the CMV IE genes. The upregulation of the HLA A2 promoter by HCVM IE gene products was shown not to be secondary to either interferon-gamma or -alpha. Previously described MHC class I regulatory or enhancer elements such as the interferon-stimulated response element (ISRE), NF-kappa B and H2TF1 binding sequences, and the interferon consensus sequence (ICS) were not required for transactivation of the A2 promoter. Rather, the only known regulatory elements in the HLA A2 promoter necessary for both basal expression and transactivation by HCVM IE gene products are the CCAAT box and TATA box motifs. These results support a model in which HCVM IE gene products act through the minimal HLA A2 promoter elements to increase gene expression.

Base Sequence↗
PubMed1993

Specific regulation of immediate early genes by patterned neuronal activity.

Electrical activity shapes development of the nervous system, presumably in part by regulating gene expression. A set of regulatory genes, immediate early genes (IEGs), which are responsive to a number of extrinsic cellular stimuli have been proposed to play a role in coupling such activity to gene expression. Using a semiquantitative polymerase chain reaction assay, we show that in dissociated mouse dorsal root ganglion neurons the expression of two IEGs, c-fos and nur/77, is differentially sensitive to patterns of electrical stimulation. Differences in c-fos activation did not correlate with the peak intracellular calcium [Ca++]i produced by the different stimulation patterns or with residual [Ca++]i following stimulation. However, the net increase in [Ca++]i (calcium time integral) was greater for the pulsed stimulus that activated c-fos (6 impulses/min), compared to the ineffective stimulus (12 impulses/2 min). This system of genes seems suited to mediating the coupling between electrical activity and other functional genes.

Action Potentials↗
PubMed2004

Cellular-resolution activity mapping of the brain using immediate-early gene expression.

Immediate-Early Genes are a class of genes that are rapidly up-regulated following neural stimulation. Due to their quality as potential activity markers in the CNS, they have been used extensively in functional mapping studies. At least three genes have been popularly used, including zif268 (Egr1, NGFI, Krox-24, or ZENK), c-fos and recently, Arc. A number of techniques have been developed in applying IEG labelling for the development of functional maps, thus overcoming some of the earlier limitations of this approach. Current developments highlight the future prospects of cellular-resolution functional activity mapping of the brain.

Animals↗
PubMed1989

Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation.

Recent studies in invertebrates indicate that a rapid genomic response to neuronal stimulation has a critical role in long-term changes in synaptic efficacy. Because several of the genes (immediately early genes; IEGs) that respond rapidly to growth factor stimulation of vertebrate cells in vitro are also activated by neuronal stimulation in vivo, attention has focused on the possibility that they play a part in synaptic plasticity in vertebrate nervous systems. Four IEGs thought to encode transcription factors, zif/268 (also termed Egr-1, NGFI-A, Krox 24), c-fos, c-jun, and jun-B are rapidly induced in the brain by seizure activity, and we have now studied the induction of these genes in a well-characterized model of synaptic plasticity in the vertebrate brain--long-term potentiation (LTP) of the perforant pathgranule cell (pp-gc) synapse in vivo. We found that high-frequency (but not low-frequency) stimulation of the pp-gc synapse markedly increases zif/268 messenger RNA (mRNA) levels in the ipsilateral granule cell neurons; mRNA of c-fos, c-jun and jun-B is less consistently increased. The stimulus frequency and intensity required to increase zif/268 mRNA levels are similar to those required to induce LTP, which is also seen only ipsilaterally, and both responses are blocked by NMDA-receptor antagonists as well as by convergent synaptic inhibitory inputs already known to block LTP. Accordingly, zif/268 mRNA levels and LTP seem to be regulated by similar synaptic mechanisms.

Afferent Pathways↗
PubMed1997

Echovirus 1 replication, not only virus binding to its receptor, VLA-2, is required for the induction of cellular immediate-early genes.

Induction of immediate-early genes c-jun, junB, and c-fos was demonstrated during echovirus 1 infection in a human osteogenic sarcoma (HOS) cell line. Tenfold induction was seen at 10 h postinfection, corresponding approximately to the end of the first replication cycle of the virus. Echovirus 1 uses VLA-2 integrin as its cellular receptor, and ligand binding by integrin is known to trigger signal transduction pathways ultimately activating immediate-early genes. In the present study, however, VLA-2 binding alone was not sufficient to induce their expression; viral replication was needed. This conclusion was based on the observations that no stimulation of the immediate-early genes occurred in the MG-63 cell line where the virus attached only to VLA-2 but was not able to replicate and that induction of these genes was observed when the HOS cells were infected with echovirus type 7, known to use a different cellular receptor. Induction was not seen in the presence of the antiviral compound WIN 54954, which evidently inhibits the uncoating but not receptor binding of echovirus 1, suggesting that viral replication triggers the activation of the immediate-early genes. The induction of these genes may have a role in viral replication and in the pathogenesis of infection.

Enterovirus B, Human↗
PubMed1996

Immediate early gene expression in response to cerebral ischemia. Friend or foe?

BACKGROUND: Cerebral ischemia is a potent modulator of gene expression. Immediate early genes undergo rapid induction after both global and focal cerebral ischemia. Many immediate early genes code for transcription factors. Additional genes, including those encoding for neurotrophic factors and neurotransmitter systems, are induced in a delayed fashion after cerebral ischemia. The functional significance of early and late gene regulation after cerebral ischemia requires further investigation. These changes may be beneficial (friend) or detrimental (foe). Many of the genes are likely neuroprotective and important for recovery, but others may be involved in ischemic cell death mediated by apoptosis. SUMMARY OF REVIEW: We review evidence that supports the hypothesis that cell death after cerebral ischemia occurs through the dual pathways of ischemic necrosis and apoptosis. CONCLUSIONS: Gene regulation, including immediate early genes, is required for programmed neuronal death after trophic factor deprivation and is predicted to be involved in apoptosis triggered by cerebral ischemia. Novel therapies following cerebral ischemia may be directed at genes mediating either recovery or apoptosis.

Animals↗
PubMed2001

Effect of cytomegalovirus immediate early gene products on endothelial cell gene activity.

OBJECTIVE: Cytomegalovirus (CMV) infection or reactivation from latency in vascular cells have been shown to contribute to atherosclerosis. CMV-infected endothelial cells (ECs) exhibit enhanced adhesion and procoagulant properties, changes compatible with processes observed in atherogenesis. The major immediate early promoter drives immediate early gene transcription. Immediate early (IE) gene products, IE72 and IE84, function as transcription factors and thereby influence expression of cellular genes, in permissive cells as well as in abortive infections, in which viral activity is limited to immediate early expression. ECs have been shown to harbor latent CMV, support abortive CMV infection and, under certain conditions, are permissive to productive viral infection. The objective of this study was to determine whether immediate early expression alone (in the absence of further progression of the virus life-cycle) results in the activation of EC genes associated with atherogenesis. METHODS: The study was conducted in an in vitro transient transfection system in human and bovine vascular ECs, with CMV immediate early gene expression vectors and plasmids containing promoter sequences of adhesion molecule, growth factor and viral promoters driving the transcription of reporter genes. RESULTS: CMV immediate early gene expression resulted in an increase in monocyte adhesion to ECs and in the relative promoter activities of cellular growth factor and adhesion molecule genes. In addition, the viral major immediate early promoter was regulated in EC by thrombin and the immediate early gene products. CONCLUSION: These results infer the possible existence of a positive feedback mechanism in the developing atherosclerotic lesion, in which enhanced immediate early gene expression leads to subsequent activation of EC genes, which might in turn result in further activation of CMV activity.

Animals↗