Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are four members of the myocyte enhancer binding factor 2 (MEF2) family of transcription factors, MEF2A, -B, -C, and -D, that have homology within an amino-terminal MADS box and an adjacent MEF2 domain that together mediate dimerization and DNA binding. MEF2A, -C, and -D have previously been shown to bind an A/T-rich DNA sequence in the control regions of numerous muscle-specific genes, whereas MEF2B was reported to be unable to bind this sequence unless the carboxyl terminus was deleted. To further define the functions of MEF2B, we analyzed its DNA binding and transcriptional activities. In contrast to previous studies, our results show that MEF2B binds the same DNA sequence as other members of the MEF2 family and acts as a strong transactivator through that sequence. Transcriptional activation by MEF2B is dependent on the carboxyl terminus, which contains two conserved sequence motifs found in all vertebrate MEF2 factors. During mouse embryogenesis, MEF2B transcripts are expressed in the developing cardiac and skeletal muscle lineages in a temporospatial pattern distinct from but overlapping with those of the other Mef2 genes. The mouse Mef2b gene maps to chromosome 8 and is unlinked to other Mef2 genes; its intron-exon organization is similar to that of the other vertebrate Mef2 genes and the single Drosophila Mef2 gene, consistent with the notion that these different Mef2 genes evolved from a common ancestral gene.
Mol Cell Biol 1996 Jul
PMID:MEF2B is a potent transactivator expressed in early myogenic lineages. 866 99

Cysteine residue 69 of the Escherichia coli Ada transcription factor, which accepts a methyl group from methylphosphotriester in methylated DNA, was substituted by each of 19 other amino acids. Only the mutant Ada (C69H), carrying a histidine substitution of Cys69, exhibited a limited degree of transactivating potential for the ada promoter in E. coli cells although the mutant protein was completely devoid of methylphosphotriester-DNA methyltransferase activity. Using a multicopy plasmid system for the expression of Ada protein, we have shown that Ada C69H has a transactivating capacity equivalent to that of wild-type Ada protein in the absence of an alkylating agent. This indicates that the zinc-binding capacity of histidine at residue 69 is likely to be sufficient for Ada to recognize and bind to the ada promoter. Furthermore, transactivation of the ada promoter by Ada C69H was enhanced up to 6-fold by treatment with methylating agents. An additional substitution was made with alanine in Ada C69H, replacing Cys321, the site for acceptance of a methyl group from O6-methylguanine and O4-methylthymine residues in DNA, with alanine. This renders the protein completely inactive as a methyltransferase but this derivative is constitutively active as a transactivator for the ada promoter. Therefore, acquisition of a methyl group at Cys321 apparently enhances the transactivating capacity of Ada protein on the ada promoter. We propose that the transcription-regulating function of Ada protein is under dual control by methylation of cysteine residues at positions 69 and 321; the former enhances DNA binding, while the latter enhances the transactivating capacity of the protein.
Mol Gen Genet 1996 Mar 20
PMID:Requirement for two conserved cysteine residues in the Ada protein of Escherichia coli for transactivation of the ada promoter. 867 55

The mechanism or mechanisms by which ras oncogenes induce morphological transformation and anchorage-independent growth are poorly understood but are thought to involve stable alterations in gene expression. We previously described a genetically dominant, mutant rat fibroblast cell line (ER-1-2) that is resistant to ras-induced anchorage-independent growth. We now describe a cell line derived from ER-1-2 cells, termed ER-1-2T, that has apparently sustained a second, dominant mutation that conferred on these cells the ability to form colonies in soft agar. Analysis of these and control cell lines demonstrated that deregulation of many of the genes commonly associated with the transformed phenotype could be dissociated from anchorage-independent growth. After infection with a ras-expressing retrovirus, both control and ER-1-2 cell lines constitutively expressed elevated levels of the c-jun, junB, fosB, c-myc, collagenase, ornithine decarboxylase, osteopontin, stromelysin, cathepsin L, and insulin-like growth factor 1 genes. These data indicate that signaling events downstream of ras were largely intact in ER-1-2 cells and that the defect in these cells lies either on a pathway separate from those that control stable, ras-mediated expression of these genes or at a point in the cell-division cycle distinct from those that control expression of the genes. In contrast, only c-jun, junB, c-myc, and ornithine decarboxylase were expressed at a significantly elevated level in ER-1-2T cells. Thus, deregulated expression of the genes analyzed was not sufficient for anchorage-independent growth. Furthermore, deregulation of most of them was also not necessary.
Mol Carcinog 1996 Jul
PMID:Dissociation of ras oncogene-induced gene expression and anchorage-independent growth in a series of somatic cell mutants. 868 49

Lateral (parasagittal) fluid-percussion brain injury of mild (1.0-1.5 atm) and moderate (2.1-2.4 atm) severity induced expression of mRNAs for the immediate early genes (IEGs) c-fos, c-jun and junB. At 5 min following mild brain injury, c-fos and junB mRNA were co-induced in the cortex ipsilateral to the impact site. Expression remained elevated up to 2 h after injury and returned to control levels by 6 h. Levels of c-fos mRNA increased in the cells of the hippocampal dentate gyrus as early as 5 min after mild brain injury and additionally in the areas CA1-3 by 30 min. By 2 h, no hippocampal c-fos mRNA was detectable. Induction of junB mRNA in the hippocampus was delayed, occurring at 30 min after injury, and remained elevated up to 2 h post injury. Increased levels of junB mRNA were also observed in the striatum ipsilateral to the injury. Increased expression of c-jun mRNA was restricted to the ipsilateral dentate gyrus and was observed at 5 min after injury and remained elevated up to 6 h. Although the temporal pattern of induction of individual IEGs after brain injury of moderate severity was similar to that observed after mild severity, moderate injury induced IEG mRNA in both injured and contralateral hemispheres. These data suggest that traumatic brain injury invokes a complex acute regional and cellular response which may involve the activation of multiple signal transduction pathways.
Brain Res Mol Brain Res 1996 Apr
PMID:Regionally and temporally distinct patterns of induction of c-fos, c-jun and junB mRNAs following experimental brain injury in the rat. 873 44

Polyomavirus large T-antigen transgenic mice develop cardiac hypertrophy characterized by an increase in atrial natriuretic factor and beta-myosin heavy chain isoform expression. The aim of this study was to examine changes in proto-oncogene expression in hypertrophied hearts from the transgenic mice. Expression of early growth response-1 (Egr-1) mRNA was detected in hearts from all 15 transgenic mice, but was not detectable in 13 control mice. Reverse transcriptase-polymerase chain reaction experiments using Egr-1-specific primers confirmed the increase in Egr-1 mRNA in enlarged hearts from the transgenic mice. Expression of c-jun, junD and Ha-ras mRNAs was increased in the transgenic hearts 3, 17 and 2.8-fold respectively. Western blots showed an increase in c-myc, c-jun and ras protein in hypertrophied transgenic hearts. Immunofluorescence analyses confirmed an increase in Egr-1 and c-jun protein in transgenic cardiomyocytes. Proliferating cell nuclear antigen, Ki-ras and HSP 90 mRNAs were decreased 22, 2.7 and 3-fold, respectively in the transgenic hearts. Not altered in most hypertrophied hearts was expression of c-fos, junB, p53, c-neu, c-myc, HSP70, HSP27, TGF-beta or IGF 1 mRNAs. Proto-oncogene and growth factor gene expression in hypertrophy induced by PVLT expression is modulated with some proto-oncogenes increased and others decreased in expression.
Mol Cell Biochem 1995 Nov 22
PMID:Molecular remodelling in hypertrophied hearts from polyomavirus large T-antigen transgenic mice. 875 Nov 59

VP16 (termed VP16-H here) of herpes simplex virus (HSV) belongs to a family of related regulatory proteins which includes VP16-B of bovine herpesvirus (BHV). We show that VP16-B, while also being a powerful transactivator of transcription dependent on Oct-1 binding sites in its target promoters, has virtually no activity on a defined VP16-H-responsive, octamer-containing target promoter. While Oct-1 binds equally well to the VP16-B-responsive and -nonresponsive sites, VP16-B interacts with Oct-1 only when Oct-1 is bound to the BHV octamer site and not when it is bound to the HSV site. We show from the analysis of chimeric proteins that the ability of VP16-B to discriminate between the Oct-1 forms depends on features of its N-terminal region. We also show from an analysis of chimeric DNA motifs that sequences that lie 3' to the POU domain-contacting region of the HSV octamer site play a role in making it unresponsive to VP16-B. Finally, we show by high-resolution hydroxyl radical footprint analysis that the conformation of Oct-l is different on the two sites. These results augment our previous report on an allosteric effect of DNA signals on the conformation of bound proteins and indicate that different conformations of the same DNA binding protein can be recognized selectively by related members of interacting regulatory proteins. The possible implications of our observations for selective gene regulation by Oct-1, a ubiquitous transcription factor, and other multimember transcription families are discussed.
Mol Cell Biol 1996 Aug
PMID:Conformational alteration of Oct-1 upon DNA binding dictates selectivity in differential interactions with related transcriptional coactivators. 875 41

We have established an expression system for full-length HIV-1 transactivator (Tat) protein in Escherichia coli. By constructing a synthetic gene for high level expression in enteric bacteria, the recombinant protein can be obtained in high yield. Fusion of the Tat sequence to an N-terminal histidine tag allows the rapid purification of the fusion protein through a single chromatographic step. After cleavage of the fusion protein with CNBr, pure Tat can be obtained through the use of a MonoS column. Reduction of the protein with Tris(2-carboxyethyl)phosphine-HCl and subsequent stepwise refolding yields biologically active Tat. Sample purity and the identity of the protein mass with the mass expected from the amino acid sequence was demonstrated by mass spectrometry. Nuclear magnetic resonance spectroscopy showed the identity of bacterially expressed and chemically synthesized Tat protein (P. Bayer et al., 1995, J. Mol. Biol. 247, 529-535). The expression of Tat in E. coli enables isotope labeling as a prerequisite for multidimensional NMR experiments toward the elucidation of the structure of the Tat-trans-activation response element complex.
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PMID:Cloning, high-yield expression in Escherichia coli, and purification of biologically active HIV-1 Tat protein. 881 37

The renin-angiotensin system controls blood pressure through the enzymatic production of the vasopressor angiotensin II (AII) from the angiotensinogen (AGT) precursor. Intravascular AII production stimulates de novo synthesis of its precursor in a positive feedback loop through increased gene expression. In this study, we investigate the effects of AII on AGT gene expression. At nanomolar concentrations, All activates transcription of the native AGT gene; this region is mapped to the AGT gene multihormone-inducible enhancer (-615 to -470). Within the multihormone-inducible enhancer, site-directed mutations of the acute-phase response element (APRE) that interfere with nuclear factor-kappa B (NF-kappa B) transcription factor binding also abolish All responsiveness. The APRE functions as a rapidly inducible All-inducible enhancer with peak reporter activity detected after a 4-h stimulation; this effect occurs only when the type 1 AII receptor is expressed. All induces sequence-specific NF-KB binding to the APRE in HepG2 nuclear extracts. Moreover, AII infusions of primary rat hepatocyte cultures produces a rapid 4-fold increase in sequence-specific NF-kappa B binding to the APRE. Antibodies against the transcriptional activator subunit, Rel A, quantitatively supershift the nucleoprotein complex, whereas antibodies to other NF-kappa B members do not, demonstrating that Rel A APRE-binding activity is AII-inducible. Transient overexpression of Rel A(1-551) activates the AGT multihormone-inducible enhancer. AII-inducible domains of Rel A were mapped by cotransfecting a chimeric GAL4-Rel A fusion protein with a reporter gene containing GAL4-binding sites. GAL4-Rel A(1-551) was an AII-inducible transactivator. Deletion of the NH(2)-terminal 254 amino acids of Rel A produces a constitutive transactivator, indicating that Rel A is activated by AII in a manner dependent on its NH(2) terminus. These studies define one mechanism for the renin-angiotensin system positive feedback loop in hepatocyctes.
Mol Endocrinol 1996 Mar
PMID:Angiotensinogen gene activation by angiotensin II is mediated by the rel A (nuclear factor-kappaB p65) transcription factor: one mechanism for the renin angiotensin system positive feedback loop in hepatocytes. 883 54

Efficient expression of the human immunodeficiency virus (HIV) genome requires the viral-encoded transactivator Tat. Tat interacts with the highly structured trans-activation-response (TAR) RNA that is found at the 5' end of all viral transcripts, and mediates the formation of transcription complexes that are capable of elongation through the entire length of the viral genome. By placing TAR immediately downstream from the P2 promoter of the mouse c-myc gene, we have previously shown that Tat can also direct transcriptional elongation through potential sites of premature termination within c-myc in transfected HeLa cells. We now demonstrate that Tat can activate c-myc transcription when TAR is positioned internally within the c-myc transcript at distances up to 353 nt downstream from the P2 promoter. We show that Tat can also activate transcription from the c-myc P1 promoter, which is located 165 nt upstream from P2 in these hybrid gene constructs. These novel findings show that Tat can activate transcription in vivo when TAR is positioned at distances up to 518 nt downstream from the site of transcriptional initiation. The ability of TAR to mediate Tat-activated transcription over distances greater than previously appreciated has important implications for the mechanism of action of Tat.
J Mol Biol 1996 Oct 18
PMID:Effect of the position of TAR on transcriptional activation by HIV-1 Tat in vivo. 889 Sep 8

The AP-1 transcription factor is a variable complex of Fos and Jun nuclear phosphoproteins that is induced in many cell types. AP-1 interacts with transcription factors of different classes, including the nuclear steroid hormone receptors, an interaction that is often mutually antagonistic and thereby serves to integrate different cellular signalling events. In addition to direct, molecular interactions between AP-1 and glucocorticoid receptor (GR), there is also evidence that the two signalling pathways may interact at different levels, but in vivo interactions of this nature have not been well characterized. We have investigated a unique cellular context for GR/AP-1 interactions, namely in the adrenal gland of the rat where the production of glucocorticoids leads to extremely high local levels of glucocorticoids, and where high constitutive AP-1 activity (as determined by in vitro DNA binding activity) has been demonstrated. We have now shown that depletion of glucocorticoid production in rats with the 11-beta-hydroxylase inhibitor, metyrapone, results in increased adrenal AP-1 activity. The demonstrated 5-fold increase is reversed by prior treatment with the glucocorticoid agonist, dexamethasone, and is largely localized to the adrenal medullary region. Further experiments have shown that c-Jun and JunD are the principal components of adrenal AP-1 in the basal state, but a change in jun-B expression appears to underly the metyrapone-induced increase in AP-1 activity. In situ hybridization analysis has shown that glucocorticoid depletion is associated with a dramatic increase in adrenal medullary junB mRNA, and using immunoblotting we have demonstrated a similar increase in nuclear levels of both the 43 kD JunB protein, and an associated phosphorylated JunB. Our use of a pharmacological intervention to demonstrate tonic suppression of adrenal medullary JunB expression by glucocorticoids has provided evidence of a nuclear mechanism that may have physiological relevance as an adaptive response to fluctuating levels of glucocorticoids.
Mol Cell Endocrinol 1996 Sep 18
PMID:Tonic suppression of adrenal AP-1 activity by glucocorticoids. 890 45


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