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Query: UNIPROT:P06889 (Mol)
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Regulation of replicative functions in the Epstein-Barr virus (EBV) genome is mediated through activation of a virally encoded transcription factor, Z (BZLF1). We have shown that the Z gene product, which binds to AP-1 sites as a homodimer and has sequence similarity to c-Fos, can efficiently activate the EBV early promoter, BMRF1, in certain cell types (i.e., HeLa cells) but not others (i.e., Jurkat cells). Here we demonstrate that the c-myb proto-oncogene product, which is itself a DNA-binding protein and transcriptional transactivator, can interact synergistically with Z in activating the BMRF1 promoter in Jurkat cells (a T-cell line) or Raji cells (an EBV-positive B-cell), whereas the c-myb gene product by itself has little effect. The simian virus 40 early promoter is also synergistically activated by the Z/c-myb combination. Synergistic transactivation of the BMRF1 promoter by the Z/c-myb combination appears to involve direct binding by the Z protein but not the c-myb protein. A 30-bp sequence in the BMRF1 promoter which contains a Z binding site (a consensus AP-1 site) is sufficient to transfer high-level lymphoid-specific responsiveness to the Z/c-myb combination to a heterologous promoter. That the c-myb oncogene product can interact synergistically with an EBV-encoded member of the leucine zipper protein family suggests c-myb is likely to engage in similar interactions with cellularly encoded transcription factors.
Mol Cell Biol 1992 Jan
PMID:The cellular oncogene c-myb can interact synergistically with the Epstein-Barr virus BZLF1 transactivator in lymphoid cells. 130 87

The nuclear gene for cytochrome c1 in Saccharomyces cerevisiae (CYT1) was localized on chromosome XV. Its upstream region was identified by functional complementation. Fusion to the lacZ reporter gene on a CEN plasmid allowed study of the effect of carbon sources and of specific deletion mutations on expression of the gene in yeast transformants. Detailed promoter analysis combined with expression studies in recipient strains defective in regulatory genes identified cis-acting sites and transcription factors involved in the regulated expression of the cytochrome c1 gene. These analyses showed that, in the presence of glucose, transcription of CYT1 is positively controlled by oxygen, presumably through the haem signal, and mediated by the HAP1-encoded transactivator. It is additionally regulated by the HAP2/3/4 complex which mediates gene activation mainly under glucose-free conditions. Basal transcription is, in part, effected by CPF1, a centromere and promoter-binding factor.
Mol Gen Genet 1992 Apr
PMID:Expression of yeast cytochrome c1 is controlled at the transcriptional level by glucose, oxygen and haem. 131 98

Exposure of rodents to light at daily times at which it can phase-shift circadian rhythms (subjective night) induces an increase in immunoreactivity for the immediate-early gene product Fos in cells of the circadian pacemaker, the suprachiasmatic nuclei (SCN). Light exposure at other phases (subjective day) does not increase Fos immunoreactivity in SCN cells, but it is not known whether this failure reflects the inability of light to induce transcription of appropriate mRNAs, or a post-transcriptional block. We used in situ hybridization studies to examine levels of mRNA in the SCN of rats exposed to light during the subjective day and subjective night. We studied levels of mRNAs for several immediate-early genes: c-fos, NGFI-A, NGFI-B, c-jun, junB and junD, before and after light exposure at these phases. Levels of mRNAs for all of the genes tested were unaffected by light exposure during the subjective day, and all were increased in response to light during the subjective night. With the exception of a weak constitutive label for junD, none of the genes were expressed in the SCN in darkness at either phase. Light-induced increases in the levels of several mRNAs in the SCN occur only during the subjective night; the mechanisms which prevent such responses during the subjective day remain unknown.
Brain Res Mol Brain Res 1992 Jun
PMID:Circadian variation in photic regulation of immediate-early gene mRNAs in rat suprachiasmatic nucleus cells. 132 9

Activation of either muscarinic cholinergic or thrombin receptors increases phosphoinositide turnover, Ca2+ mobilization, and redistribution of protein kinase C and induces rapid transient increases in c-fos mRNA and c-jun mRNA in 1321N1 cells. To determine whether the increases in c-fos and c-jun mRNA induced by carbachol and thrombin are sufficient to stimulate AP-1-mediated transactivation, 1321N1 cells were transfected with a reporter carrying two copies of the tetradecanoyl phorbol acetate response element and the firefly luciferase gene. Thrombin was significantly more effective than carbachol at stimulating AP-1-mediated transactivation. To identify the factors underlying the difference in AP-1 activity induced by carbachol and thrombin, members of the fos and jun families which encode components of AP-1 were examined. Carbachol and thrombin have similar effects on expression of c-fos, fosB, fra-2, junB, and junD, both acutely and over a 24-h time course. However, whereas carbachol leads only to transient induction of c-jun (maximal at 0.5 h), thrombin induces a biphasic increase in c-jun mRNA--an initial peak at 0.5 h and a second, more-prolonged increase at 12 h. Thrombin but not carbachol also induces a late increase in fra-1 mRNA, which peaks at 12 h. The secondary increase in c-jun mRNA is associated with marked increases in c-Jun protein levels and AP-1 DNA-binding activity. The late induction of c-jun and fra-1 mRNA can be prevented by adding the antagonist hirudin 30 min after thrombin, which results in loss of thrombin-stimulated increases in c-Jun protein, AP-1 DNA-binding activity, and AP-1-mediated transactivation. These findings suggest that rapid and transient conduction of c-fos and c-jun mRNA is insufficient to induce prominent changes in gene transcription, while the sustained increase in c-jun mRNA and perhaps the late induction of fra-1 mRNA are required for generation of AP-1 DNA-binding activity and transactivation through AP-1.
Mol Cell Biol 1992 Oct
PMID:Biphasic increase in c-jun mRNA is required for induction of AP-1-mediated gene transcription: differential effects of muscarinic and thrombin receptor activation. 132 61

Neoplastic transformation and transcriptional activation by activator protein-1 (AP-1) complex are stimulated by tumor-promoting agents in promotion-sensitive (P+) but not promotion-resistant (P-) mouse epidermal JB6 cells in culture. This implicates AP-1 as a specific regulator of signal transduction pathways in the promotion phase of neoplastic transformation. We therefore hypothesized that the defective P- responsiveness may be due to limiting levels of AP-1 protein components in those cells. In this investigation, steady-state levels of AP-1 protein components were measured by immunoprecipitating proteins from 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated P+ and P- cells to discern what may limit the AP-1 response. Whereas the AP-1 proteins junB, junD, and fosB did not show differential basal or TPA-inducible levels in P+ and P- cells, a 46-kDa species precipitated by anti-fra-1 antibody was TPA-inducible in P- cells but not in P+ cells, and c-jun protein was present at higher levels in TPA-treated and untreated P+ cells than in P- cells. These data raise the possibility that the 46-kDa fra-1-related protein may be a negative modulator of AP-1 activity and suggest that elevated levels of this 46-kDa species and limiting levels of c-jun may significantly impair AP-1 function or transformation response in P- cells or both.
Mol Carcinog 1992
PMID:12-O-tetradecanoylphorbol-13-acetate--induced levels of AP-1 proteins: a 46-kDa protein immunoprecipitated by anti-fra-1 and induced in promotion-resistant but not promotion-sensitive JB6 cells. 144 22

The angiotensinogen gene encodes the precursor protein for the potent vasoconstrictor angiotensin II. Although the gene is expressed in several tissues, the liver is the major source of circulating protein. In previous in-vivo studies we have found that a mini-gene containing 750 bp of 5'-flanking sequence is transcribed in a manner which largely parallels the expression of the endogenous gene. In this report, we characterized conserved elements in the promoter region, in order to determine their role in the transcription of the angiotensinogen gene. Constructs fused to the chloramphenicol acetyl transferase (CAT) reporter gene were transfected into hepatocarcinoma Hep G2 cells as well as into nonhepatic cell lines. We found that 5'-deletion mutant constructs, containing sequences from +25 to -90 bp and -321 to -750 bp, were each able to activate transcription. These constructs contain the TATA box and core promoter sequences, including an Sp1-binding site, and two glucocorticoid responsive elements respectively. In the non-hepatic cell lines, HeLa and Jeg-3, we found that the constructs were transcribed at a much lower rate when compared with the expression of a plasmid containing the Rous sarcoma virus long terminal repeat fused to the CAT gene. Constructs which included sequence 5' to -244 were oestrogen inducible. An element which is conserved between rodent and human angiotensinogen promoters is contained within a sequence which is oestrogen responsive, while another binds the liver-enriched transcriptional activator hepatocyte nuclear factor 1. However, the role of this transactivator in the transcription of angiotensinogen remains uncertain.
J Mol Endocrinol 1992 Aug
PMID:The function of conserved elements in the promoter of the mouse angiotensinogen gene. 151 23

Transforming growth factor beta (TGF-beta) is the name of a group of closely related polypeptides characterized by a multiplicity of effects, including regulation of extracellular proteolysis and turnover of the extracellular matrix. Its cellular mechanism of action is largely unknown. TGF-beta 1 is a strong and fast inducer of type 1 plasminogen activator inhibitor gene transcription. We have identified a TGF-beta 1-responsive element in the 5'-flanking region of the human type 1 plasminogen activator inhibitor gene and shown that it is functional both in its natural context and when fused to a heterologous nonresponsive promoter. Footprinting and gel retardation experiments showed that two different nuclear factors, present in extracts from both TGF-beta 1-treated and nontreated cells, bind to adjacent sequences contained in the responsive unit. A palindromic sequence binds a trans-acting factor(s) of the CCAAT-binding transcription factor-nuclear factor I family. A partially overlapping dyad symmetry interacts with a second protein that much evidence indicates to be USF. USF is a transactivator belonging to the basic helix-loop-helix family of transcription factors. Mutations which abolish the binding of either CCAAT-binding transcription factor-nuclear factor I or USF result in reduction of transcriptional activation upon exposure to TGF-beta 1, thus showing that both elements of the unit are necessary for the TGF-beta 1 response. We discuss the possible relationship of these findings to the complexity of the TGF-beta action.
Mol Cell Biol 1992 Apr
PMID:Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene. 154 30

The proteins encoded by cellular and viral src genes are believed to be involved in the transmission of mitogenic signals, the nuclear recipients of which are largely unknown. In this work, we report that four different v-src-transformed cell lines from three different species possess elevated levels of junB transcripts. Transient expression of junB promoter-chloramphenicol acetyltransferase constructs in NIH 3T3 cells was used to demonstrate that the increase in junB transcripts was specifically associated with v-src expression and could not be recapitulated with a c-src, v-H-ras, or v-raf expression vector. Deletion mutants were used to localize the v-src-responsive region in the junB promoter to a 121-nucleotide region encompassing the CCAAT and TATAA elements. This region is distinct from one in the 5' untranslated region of the junB gene which is required to maintain its high-level basal expression. Point mutagenesis of the junB TATAA box completely abolished v-src responsiveness, suggesting that proteins which bind to this element are modified by src transformation. Several v-src and c-src mutants were used to demonstrate that elevated tyrosine kinase activity of src proteins is required for the observed effects on junB expression. Finally, homology between the TATAA box regions of junB and the unrelated but src-responsive gene 9E3/CEF-4 suggests that modulation of gene activity through proteins which bind to this region may be a recurrent, although not exclusive, theme in src transforming action. Our results suggest that src proteins may modulate some nuclear effectors through pathways not involving cellular ras or raf gene products.
Mol Cell Biol 1992 Aug
PMID:Regulation of the junB gene by v-src. 163 Apr 51

The AP1 transcriptional complex is a heterodimer composed of proteins encoded by the fos and jun proto-oncogene families. Changes in the concentration and composition of AP1 occur after cells are perturbed in a variety of different ways (Curran, in Reddy et al., eds. "The Oncogene Handbook," Amsterdam: Elsevier, pp 307-325, 1988; Sonnenberg et al., Neuron 3:359-365, 1989). Transient changes in AP1 content presumably result in altered expression of AP1-regulated target genes, that help to mediate the cell's long-term response to changes in its environment. One factor that may be important in determining which target genes are regulated by AP1 in a given context is the identity of the jun family member present in the complex (Chiu et al., Cell 59:979-986, 1989; Schutte et al., Cell 59:987-997, 1989). Fos induction has been demonstrated after binding of beta-adrenergic ligands to their cell surface receptors (Barka et al., Mol Cell Biol 6:2984-2989, 1986; Gubits et al., Mol Brain Res 6: 39-45, 1989; Arenander et al., J Neurosci Res 24: 107-114, 1989; Mocchetti et al., Proc Natl Acad Sci USA 86:3891-3895, 1989). However, the response of the jun gene family to this treatment has not been reported. We have therefore examined the effect of beta-adrenergic receptor activation on the expression of c-fos, c-jun, and junB mRNA levels in C6 glioma cells. Our results indicate that c-fos and junB mRNA levels are increased by 52- and 2.7-fold, respectively, after 45 min of isoproterenol (IPR) treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beta-adrenergic treatment of C6 glioma cells produces opposite changes in c-fos and c-jun mRNA levels. 168 82

Immediate early genes (IEGs) are a class of genes that show rapid and transient but protein synthesis-independent increases in expression to extracellular signals such as growth factors and neurotransmitters. Many IEGs code for transcription factors that have been suggested to govern the growth and differentiation of many cell types by regulating the expression of other genes. IEGs are expressed in adult neurons both constitutively and in response to afferent activity, and it has been suggested that during learning, IEGs may play a role in the signal cascade, resulting in the expression of genes critical for the consolidation of long-term memory. Long-term potentiation (LTP) is a persistent, activity-dependent form of synaptic plasticity that stands as a good candidate for the mechanism of associative memory. A number of IEGs coding for transcription factors have been shown to transiently increase transcription in the dentate gyrus of rats following LTP-inducing afferent stimulation. These include zif/268 (also termed NGFI-A, Krox-24, TIS-8, and egr-l), c-fos-related genes, c-jun, junB, and junD. Of these, zif/268 appears to be the most specifically related to LTP since it is evoked under virtually all LTP-inducing situations and shows a remarkably high correlation with the duration of LTP. There are a number of outstanding questions regarding the role of zif/268 and other IEGs in LTP, including which second messenger systems are important for activating them, which "late effector" genes are regulated by them, and the exact role these genes play, if any, in the stabilization and maintenance of LTP.
Mol Neurobiol 1991
PMID:The role of immediate early genes in the stabilization of long-term potentiation. 168 55


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