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Biomedical subjects

T Curran

Publications and source records attributed to T Curran.

At least 163 records · Page 9Linked to original sources
PubMed1989

Regulation of proenkephalin by Fos and Jun.

Fos and Jun form a heterodimeric complex that associates with the nucleotide sequence motif known as the AP-1 binding site. Although this complex has been proposed to function as a transcriptional regulator in neurons, no specific target gene has yet been identified. Proenkephalin mRNA increased in the hippocampus during seizure just after an increase in c-fos and c-jun expression was detected. Fos-Jun complexes bound specifically to a regulatory sequence in the 5' control region of the proenkephalin gene. Furthermore, c-fos and c-jun stimulated transcription from this control region synergistically in transactivation assays. These data suggest that the proenkephalin gene may be a physiological target for Fos and Jun in the hippocampus and indicate that these proto-oncogene transcription factors may play a role in neuronal responses to stimulation.

Animals↗
PubMed1989

Parallel association of Fos and Jun leucine zippers juxtaposes DNA binding domains.

The protein products of the fos and jun proto-oncogenes form a heterodimeric complex that participates in a stable high affinity interaction with DNA elements containing AP-1 binding sites. The effects of deletions and point mutations in Fos and Jun on protein complex formation and DNA binding have been examined. The data suggest that Fos and Jun dimerize via a parallel interaction of helical domains containing a heptad repeat of leucine residues (the leucine zipper). Dimerization is required for DNA binding and results in the appropriate juxtaposition of basic amino acid regions from Fos and Jun, both of which are required for association with DNA.

Amino Acid Sequence↗
PubMed1989

Glutamate receptor agonists increase the expression of Fos, Fra, and AP-1 DNA binding activity in the mammalian brain.

Administration of convulsant doses of Metrazole (pentylenetetrazol) and picrotoxin, as well as maximal electroshock, results in a rapid but transient increase in c-fos mRNA in mouse brain. Elevation of c-fos mRNA is followed by the accumulation and subsequent disappearance of Fos, the protein encoded by c-fos. In addition, immunoblots reveal the induction of two additional proteins that are antigenically related to Fos (Fra, Fos-related antigens). Fos and the various Fra appear and disappear in a staggered manner over an 8 hour period, such that at longer times after stimulation the brain contains no Fos but relatively large amounts of Fra (the latter being designated here by their apparent molecular weights, Fra-46K and Fra-35K). Previous studies have established that Fos, as well as several Fra, contribute to transcription factor AP-1 nucleoprotein complexes along with Jun, the product of the jun proto-oncogene. The appearance in brain of Fos and Fra coincides with a protracted increase in total AP-1 DNA binding activity, indicating that all the Fos-like proteins can participate in AP-1 complexes. Furthermore, the molecular composition of these complexes alters with time after stimulation. The induction of c-fos by Metrazole is blocked or attenuated by known anticonvulsants such as diazepam and valproate as well as the N-methyl-D-aspartate (NMDA) receptor antagonists, 2-amino-5-phosphonovaleric acid (APV) and MK-801. This suggests that fos induction might involve stimulation of a glutamate receptor. This conclusion was strengthened by the observations that two glutamate receptor agonists, kainic acid and NMDA, induced c-fos expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Stimulus-transcription coupling in neurons: role of cellular immediate-early genes.

Excitation of neurons results in a series of finely orchestrated responses that occur over a time frame ranging from fractions of a second to hours or days. In the short term, stimulation evokes an array of biochemical and biophysical events that represent the execution of the neurophysiological phenotype of a particular cell. These processes, which contribute to the overall behavior of a neural circuit, do not require de novo protein synthesis. In contrast, stimulation is also linked to long-term phenotypic changes that require alterations in gene expression. Thus, one or more mechanisms must exist that couple cell-surface stimuli to the transcriptional regulatory apparatus of the neuron. In this article James Morgan and Tom Curran detail a stimulus-transcription coupling cascade, involving the products of the proto-oncogenes, c-fos and c-jun, that operates in many cell types including neurons.

Animals↗
PubMed1989

Dynamic alterations occur in the levels and composition of transcription factor AP-1 complexes after seizure.

Seizure causes a rapid and protracted increase in transcription factor AP-1 levels in the brain. The composition of AP-1 nucleoprotein complexes changes with time after seizure as a result of the sequential appearance and disappearance of Fos and several Fos-related proteins. Although these changes occur over an 8 hr time period, they are triggered by 15 min of seizure. Alterations in the levels and composition of transcription factors may represent one of the molecular mechanisms underlying neuronal adaptation.

Animals↗
PubMed1989

The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes.

fra-1 encodes a serum-inducible protein (Fra-1) that is antigenically related to Fos. We have characterized Fra-1 expression in serum-stimulated cells using antibodies raised against several regions of this protein. Fra-1, expressed transiently in COS cells or in serum-stimulated rat fibroblasts, undergoes extensive post-translational modification, primarily by phosphorylation of serine residues. It is present in both the nucleus and the cytoplasm and participates in a protein complex with Jun. Using proteins synthesized in reticulocyte lysates, we have shown that Fra-1, like Fos, binds to the AP-1 recognition element cooperatively with Jun. A truncated Fra-1 protein that contains the leucine zipper region but not an adjacent basic amino acid domain, complexes with Jun in vitro but fails to bind AP-1 oligonucleotides. These results demonstrate that Fra-1 contributes to the DNA-binding activity ascribed to transcription factor AP-1.

Animals↗
PubMed1989

Calcium and proto-oncogene involvement in the immediate-early response in the nervous system.

Depolarization of neurons either in culture or in vivo results in the rapid, calcium-dependent induction of several, so-called, immediate-early genes; the prototypes being c-fos and c-jun. The proteins encoded by c-jun, c-fos, and several fos-related genes all participate in a complex that interacts with the AP-1 consensus DNA sequence, previously shown to be important for the "transcriptional activation" of certain genes. Thus it is proposed that neuronal stimulation, via elevated intracellular calcium, leads to the induction of a series of genes, some of which encode proteins involved in transcriptional regulation, that contribute to long-term adaptive and plastic responses. Surprisingly, the molecular composition of the brain AP-1 binding complex varies with time after stimulation. This is because some of the inducible Fos-related proteins accumulate with much slower kinetics than Fos itself and only appear in significant amounts when Fos has disappeared. Of some considerable interest is the result these compositional alterations have upon the transcriptional activity of the AP-1 complex. Given the foregoing findings we consider some of the possible implications this might have for aging and neurodegenerative disorders particularly with regard to alterations in cellular calcium homeostasis.

Animals↗
PubMed1989

Nobel oncogenes.

Explore the source record for details and available documents.

Animals↗
PubMed1989

The carboxy terminus of the viral Jun oncoprotein is required for complex formation with the cellular Fos protein.

The products of the proto-oncogenes c-jun and c-fos are known to form a complex in vivo. Complex formation appears to stabilize protein-DNA interactions and is thought to play an important functional role in transcriptional regulation. Here we show that the viral Jun oncoprotein, which differs structurally from cellular Jun, is also capable of complex formation with Fos. Thus the oncogenic potency of viral Jun is unlikely to be due to an altered affinity for Fos. We have also defined, by deletion analysis, the domain of v-Jun responsible for complex formation to reside in the carboxy terminus encompassing the leucine zipper motif. We find that complex formation with c-Fos does not occur with v-Jun deletions affecting one or more leucine residues in the zipper domain. Our results are consistent with the hypothesis that the leucine zipper mediates Jun-Fos interaction.

DNA↗
PubMed1988

Expression of c-fos protein in brain: metabolic mapping at the cellular level.

The proto-oncogene c-fos is expressed in neurons in response to direct stimulation by growth factors and neurotransmitters. In order to determine whether the c-fos protein (Fos) and Fos-related proteins can be induced in response to polysynaptic activation, rat hindlimb motor/sensory cortex was stimulated electrically and Fos expression examined immunohistochemically. Three hours after the onset of stimulation, focal nuclear Fos staining was seen in motor and sensory thalamus, pontine nuclei, globus pallidus, and cerebellum. Moreover, 24-hour water deprivation resulted in Fos expression in paraventricular and supraoptic nuclei. Fos immunohistochemistry therefore provides a cellular method to label polysynaptically activated neurons and thereby map functional pathways.

Animals↗
PubMed1988

Fos-associated protein p39 is the product of the jun proto-oncogene.

The Fos protein complex and several Fos-related antigens (FRA) bind specifically to a sequence element referred to as the HeLa cell activator protein 1 (AP-1) binding site. A combination of structural and immunological comparisons has identified the Fos-associated protein (p39) as the protein product of the jun proto-oncogene (c-Jun). The p39/Jun protein is one of the major polypeptides identified in AP-1 oligonucleotide affinity chromatography extracts of cellular proteins. These preparations of AP-1 also contain Fos and several FRA's. Some of these proteins bind to the AP-1 site directly whereas others, like Fos, appear to bind indirectly via protein-protein interactions. Cell-surface stimulation results in an increase in c-fos and c-jun products. Thus, the products of two protooncogenes (and several related proteins), induced by extracellular stimuli, form a complex that associates with transcriptional control elements containing AP-1 sites, thereby potentially mediating the long-term responses to signals that regulate growth control and development.

Cell Transformation, Neoplastic↗
PubMed1988

A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization.

Egr-1 is an early growth response gene that displays fos-like induction kinetics in fibroblasts, epithelial cells, and lymphocytes following mitogenic stimulation. Sequence analysis of murine Egr-1 cDNA predicts a protein with three DNA binding zinc fingers. The human EGR1 gene maps to chromosome 5 (bands 5q23-31). Egr-1 mRNA increases dramatically during cardiac and neural cell differentiation, and following membrane depolarization both in vitro and in vivo. Thus, Egr-1 and c-fos are often coregulated with strikingly similar kinetics. These results, in conjunction with the Egr-1 primary structure, suggest that Egr-1 may function as a transcriptional regulator in diverse biological processes.

Amino Acid Sequence↗
PubMed1988

The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites.

The Fos protein complex and several Fos-related antigens bind directly or indirectly to a common sequence element that is similar to the consensus binding site for HeLa cell activator protein 1 (AP-1). This element is present in a negative regulatory sequence in the differentiation-sensitive adipocyte gene, aP2; in a transcriptional enhancer for the Gibbon ape leukemia virus; and in a region of the human immunodeficiency virus (HIV) long terminal repeat partially characterized as a negative regulatory element. The protein level and binding activity of Fos and Fos-related antigens increase rapidly after calcium ionophore treatment of a CD4+ human lymphoblast cell line, H9. These data suggest that several proteins may associate with the AP-1 binding site. Moreover, temporally regulated control of the level of each protein could represent a mechanism for modulation of these putative mediators of gene expression.

Base Sequence↗
PubMed1988

Common DNA binding site for Fos protein complexes and transcription factor AP-1.

The adipocyte P2 (aP2) gene contains a regulatory element, FSE2, that functions during adipocyte differentiation and binds a protein complex containing the product of the fos proto-oncogene (Fos). We show here that the quantitative and qualitative nature of the FSE2 binding complex closely reflects the status of Fos expression within a given cell type. There is a dramatic increase in the FSE2 binding complex when Fos levels are induced with serum, benzodiazepine, and nerve growth factor or are expressed from a v-fos gene. Immunoblotting analysis of DNA retardation gels indicates a comigration of FSE2 complex with the predominant Fos species. Using a combination of mutational analyses of FSE2 and competition for binding with related sequences, we show that the Fos complex recognizes DNA containing the sequence TGACTCA, previously identified as the consensus binding site for the transcription factors AP-1 in mammalian cells and GCN4 in yeast. The simultaneous presence in cell extracts of proteins related to both AP-1 and Fos with similar sequence recognition properties was demonstrated by photo-cross-linking to FSE2 DNA and immunoprecipitating with antibodies directed toward c-fos or v-jun. These results suggest a functional relationship between Fos and AP-1.

Adipose Tissue↗
PubMed1988

Regulation of proto-oncogenes in rat parotid acinar cells in vitro after stimulation of beta-adrenergic receptors.

Stimulation of beta-adrenoreceptors in rat parotid acinar cells in vitro by the beta-adrenergic agonist isoproterenol induces steady-state levels of c-fos mRNA and c-fos protein in these cells. A dramatic increase in the steady-state levels of c-fos mRNA was observed at 60 min, followed by a decrease at 2 h with a second peak at 4 h. c-fos induction in rat parotid acinar cells in vitro seems to be mediated by cAMP. Increased levels of p53 and c-myc mRNA were detected only at 60 min. c-abl and c-sis were also induced by isoproterenol but in a pattern different from that seen with c-fos. c-abl was the only oncogene in rat parotid gland which showed increased expression after chronic isoproterenol treatment of rats. In rat parotid acinar cells we observed no correlation between DNA synthesis and c-fos induction.

Animals↗
PubMed1988

Calcium as a modulator of the immediate-early gene cascade in neurons.

Increases in intraneuronal free calcium result in the rapid, transient, induction of the fos and jun proto-oncogenes. In PC12 cells, induction may be elicited either by membrane depolarization or by direct activation of voltage-dependent calcium channels with BAY K 8644 both of which provoke an influx of calcium. The calmodulin pathway appears to link the elevated intracellular calcium to gene induction. In the brain, c-fos and c-jun may be induced by elevated neuronal activity such as occurs during pentylenetetrazole (PTZ) seizures. The N-methyl-D-aspartate (NMDA) form of the glutamate receptor, which can directly gate calcium, plays a role in the induction of c-fos expression in PTZ seizures. In addition, NMDA can directly stimulate c-fos in the brain. Fos and Jun form a noncovalent nucleoprotein complex that binds to the consensus recognition sequence of the AP-1 transcription factor. Thus in a larger picture we envisage Fos and Jun as members of a concerted stimulus-transcription coupling pathway that links alterations in external stimuli to long term adaptive responses. In this context Fos, Jun and the other immediate-early genes should be viewed as third messengers which are regulated by second messengers such as intracellular calcium.

Animals↗