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Query: UNIPROT:P06889 (Mol)
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Many properties of skeletal muscle cells are closely regulated by motor nerves. Neuromuscular synaptic transmission (including the 'activity' it triggers) mediates many of these effects, while denervation results in a different spectrum of muscle cell changes. However, little is known about the early regulatory events that occur in mature muscle cells in response to muscle activity or denervation. We have examined the effects of motor nerve stimulation and denervation on the expression of 4 immediate early genes (IEGs)--c-jun, junB, zif268, and nur77--in mature mouse gastrocnemius muscle. Electrical stimulation of the sciatic nerve in a pattern of brisk intermittent exercise induced a marked rise in zif268 and c-jun mRNA levels within 45 min, a minimal rise in junB, and no change in nur77 mRNA levels. By contrast, surgical denervation resulted in a marked increase of c-jun, a slight rise in junB, and no change in nur77 or zif268 mRNA levels. These findings show that neural stimulation and denervation lead to differential patterns of IEG expression. The selectivity of these patterns suggests that differential IEG expression may play an important role in regulating the specific phenotypic changes in skeletal muscles that result from denervation, innervation, and various patterns of stimulation.
Brain Res Mol Brain Res 1993 May
PMID:Nerve stimulation and denervation induce differential patterns of immediate early gene mRNA expression in skeletal muscle. 849 83

Activation of immediate-early gene expression has been associated with mitogenesis, differentiation, nerve cell depolarization, and recently, terminal differentiation processes and programmed cell death. Previous evidence also suggested that immediate-early genes play a role in the physiology of the lungs (J. I. Morgan, D. R. Cohen, J. L. Hempstead, and T. Curran, Science 237:192-197, 1987). Therefore, we analyzed c-fos expression in adult and developing lung tissues. Seizures elicited by chemoconvulsants induced expression of mRNA for c-fos, c-jun, and junB and Fos-like immunoreactivity in lung tissue. The use of pharmacological antagonists and adrenalectomy indicated that this increased expression was neurogenic. Interestingly, by using a fos-lacZ transgenic mouse, it was shown that Fos-LacZ expression in response to seizure occurred preferentially in clusters of epithelial cells at the poles of the bronchioles. This was the same location of Fos-LacZ expression detected during early lung development. These data imply that pharmacological induction of immediate-early gene expression in adult mice recapitulates an embryological program of gene expression.
Mol Cell Biol 1993 Jun
PMID:Regulation of proto-oncogene expression in adult and developing lungs. 849 49

Antioncogene product p53 is a transcriptional transactivator. To investigate how p53 stimulates transcription, we examined the interaction of p53 with general transcription factors in vitro. We found that p53 binds directly to the human TATA box-binding polypeptide (TBP). We also observed a direct interaction between p53 and purified holo-TFIID, a complex composed of TBP and a group of TBP-associated polypeptides known as TAFs. The p53 binding domain on TBP was mapped to the conserved region of TBP, including residues 220 to 271. The TBP binding domain on p53 was mapped to the p53 activation domain between residues 20 and 57. To analyze the significance of the p53-TBP interaction in p53 transactivation, we compared the ability of Gal4-p53 fusion proteins to bind to TBP in vitro and to activate transcription in transient transfection assays. Fusion proteins which bound to TBP activated transcription, and those that did not bind to TBP did not activate transcription to a detectable level, suggesting that a direct interaction between TBP and p53 is required for p53 transactivation. We also found that inclusion of residues 93 to 160 of p53 in a Gal4-p53 fusion repressed transcriptional activation 100-fold. Consequently, this region of p53 inhibits transcriptional activation by the minimal p53 activation domain. Highest levels of activation were observed with sequences 1 to 92 of p53 fused to Gal4, even though this construct bound to TBP in vitro with an affinity similar to that of other Gal4-p53 fusion proteins. We conclude that TBP binding is necessary for p53 transcriptional activation and that p53 sequences outside the TBP binding domain modulate the level of activation.
Mol Cell Biol 1993 Jun
PMID:The p53 activation domain binds the TATA box-binding polypeptide in Holo-TFIID, and a neighboring p53 domain inhibits transcription. 849 52

The p53 tumor suppressor gene product is a sequence-specific DNA-binding protein that is necessary for the G1 arrest of many cell types. Consistent with its role as a cell cycle checkpoint factor, p53 has been shown to be capable of both transcriptional activation and repression. Here we show a new potential role for p53 as a DNA-binding-dependent regulator of DNA replication. Constructs containing multiple copies of the ribosomal gene cluster (RGC) p53 binding site cloned on the late side of the polyomavirus origin were used in in vitro replication assays. In the presence of p53, the replication of these constructs was strongly inhibited, while the replication of constructs containing a mutant version of the RGC site was not affected by p53. Several tumor-derived mutant p53 proteins were unable to inhibit replication of the construct with wild-type RGC sites. Additionally, the transactivator GAL4-VP16 was unable to inhibit replication of a construct containing GAL4 binding sites adjacent to the polyomavirus origin. We also show that the inhibition by p53 can occur from sites cloned as far as 600 bp from the origin. Preincubation experiments suggest that p53 inhibits replication at a step mediated by ATP, possibly by inhibiting the binding of polyomavirus T antigen to the core origin. The presence of an endogenous p53 binding site in the polyomavirus origin suggests potential mechanisms for the observed inhibition.
Mol Cell Biol 1995 Dec
PMID:p53 inhibits DNA replication in vitro in a DNA-binding-dependent manner. 852 20

Bacillus anthracis plasmid pXO1 carries the structural genes for the three anthrax toxin proteins, cya (edema factor), lef (lethal factor), and pag (protective antigen). Expression of the toxin genes by B. anthracis is enhanced during growth under elevated levels of CO2. This CO2 effect is observed only in the presence of another pXO1 gene, atxA, which encodes a transactivator of anthrax toxin synthesis. Here we show that transcription of atxA does not appear to differ in cells grown in 5% CO2 compared with cells grown in air. Using a new efficient method for gene replacement in B. anthracis, we constructed an atxA-null mutant in which the atxA-coding sequence on pXO1 is replaced with an omega km-2 cassette. Transcription of all three toxin genes is decreased in the absence of atxA. The pag gene possesses two apparent transcription start sites, P1 and P2; only transcripts with 5' ends mapping to P1 are decreased in the atxA-null mutant. Deletion analysis of the pag promoter region indicates that the 111 bp region upstream of the P1 site is sufficient for atxA-mediated activation of this transcript. The cya and lef genes each have one apparent start site for transcription. Transcripts with 5' ends mapping to these sites are not detected in the atxA-null mutant. The atxA-null mutant is avirulent in mice. Moreover, the antibody response to all three toxin proteins is decreased significantly in atxA-null mutant-infected mice. These data suggest that the atxA gene product also regulates toxin gene expression during infection.
Mol Microbiol 1995 Jun
PMID:The atxA gene product activates transcription of the anthrax toxin genes and is essential for virulence. 857 51

The Sry gene functions as a genetic switch initiating testicular development of the indifferent mammalian gonad. The Mus musculus molossinus Sry open reading frame (ORF) encodes a 395-amino acid transcription factor (mSry) that specifically binds and bends DNA through its N-terminal HMG domain and activates transcription through its long C-terminal (residues 144-366) glutamine/histidine-rich activation domain. The M. m. domesticus Sry ORF encodes a highly homologous, truncated protein (dSry) of approximately 230 amino acids, and the molecular basis for truncation is a point mutation that creates an amber stop codon within the activation domain. The mSry protein activates transcription of a Sry-responsive reporter gene in HeLa cells, but dSry does not. Gene swapping and in vitro DNA binding experiments revealed that lack of transcriptional activation by dSry was not the result of polymorphisms within the first 137 amino acids of the protein. Direct analysis of the C-terminal glutamine/histidine-rich domain revealed that dSry lacked a functional transcriptional activation domain. Fusion of the GAL4 DNA-binding domain to the C-terminal deletion mutants of the GAL4-mSry chimeric protein indicated that residues 263-345 of the glutamine/histidine-rich domain were necessary for high level transactivation. Furthermore, readthrough of the premature amber stop codon by transfer RNA suppression resulted in a strong GAL4-dSry transactivator. This demonstrated that the premature stop codon is the only polymorphism responsible for the inability of the dSry glutamine/histidine-rich region to transactivate.
Mol Endocrinol 1995 Dec
PMID:Functional comparison of the Mus musculus molossinus and Mus musculus domesticus Sry genes. 861 1

Expression of the rat CYP2C12 gene is liver specific and is induced by GH at the transcriptional level. In primary cultures of rat hepatocytes, GH inducibility of CYP2C12 and the presence of C/EBP alpha protein were demonstrated to be equally dependent on attachment of the cells to an extracellular matrix gel (Matrigel). Transient transfection of a C/EBP alpha expression vector into hepatocytes, cultured without Matrigel, increased the cellular P4502C12 messenger RNA levels 10-fold. Cotransfection studies using deletion constructs of the CYP2C12 promoter fused to the luciferase reporter gene localized the C/EBP alpha response to the region -250 to -180. Sequence comparisons and deoxyribonuclease I footprinting using rat liver nuclear extracts indicated two potential C/EBP binding sites in this region. Mutagenesis of the most upstream element (-229 to -207) abolished transactivation by C/EBP alpha. Using gel mobility supershift assays, this element was demonstrated to bind C/EBP alpha and C/EBP beta in liver nuclear extracts and in lysates from hepatocytes cultured on Matrigel. GH treatment of the cells did not alter the C/EBP protein levels or the C/EBP-binding activity to this element. Neither did GH increase the expression of CYP2C12 reporter gene constructs regardless of the presence of different amounts of cotransfected C/EBP alpha. We conclude that C/EBP alpha is a potent transactivator of the CYP2C12 gene and most likely contributes to its liver-specific expression. Although the results presented here do not exclude the possibility of a GH-enhanced transactivating ability of C/EBP alpha, the mechanism of GH-induced levels of P4502C12 is not through increased levels of C/EBP alpha or via enhanced DNA-binding activity of this transcription factor.
Mol Endocrinol 1995 Dec
PMID:CCAAT/enhancer-binding protein-alpha-dependent transactivation of CYP2C12 in rat hepatocytes. 861 13

The far-upstream element-binding protein (FBP) is one of several recently described factors which bind to a single strand of DNA in the 5' region of the c-myc gene. Although cotransfection of FBP increases expression from a far-upstream element-bearing c-myc promoter reporter, the mechanism of this stimulation is heretofore unknown. Can a single-strand-binding protein function as a classical transactivator, or are these proteins restricted to stabilizing or altering the conformation of DNA in an architectural role? Using chimeric GAL4-FBP fusion proteins we have shown that the carboxyl-terminal region (residues 448 to 644) is a potent transcriptional activation domain. This region contains three copies of a unique amino acid sequence motif containing tyrosine diads. Analysis of deletion mutants demonstrated that a single tyrosine motif alone (residues 609 to 644) was capable of activating transcription. The activation property of the C-terminal domain is repressed by the N-terminal 107 amino acids of FBP. These results show that FBP contains a transactivation domain which can function alone, suggesting that FBP contributes directly to c-myc transcription while bound to a single-strand site. Furthermore, activation is mediated by a new motif which can be negatively regulated by a repression domain of FBP.
Mol Cell Biol 1996 May
PMID:A unique transactivation sequence motif is found in the carboxyl-terminal domain of the single-strand-binding protein FBP. 862 94

The mouse mammary tumor virus (MMTV) promoter is transcriptionally silent prior to hormonal induction, partly because its organization into phased nucleosomes precludes access of transcription factors to their cognate sites. A T47D-derived cell line carrying a single integrated copy of the MMTV promoter exhibited a positioned nucleosome, which prevented binding of nuclear factor I (NFI). To study the molecular mechanisms controlling promoter accessibility we have made use of a strong chimeric transactivator, NFI-VP16, composed of NFI linked to the transactivation function of VP16. T47D cells transiently transfected with an MMTV-CAT reporter show little transcription even after cotransfection of an expression vector for NFI-VP16. However, a truncated MMTV promoter, lacking the hormone regulatory region (HRR) was transactivated by cotransfected NFI-VP16. The repressive effect of the HRR was not due to binding of a sequence-specific transcriptional repressor, and was evident with the DEAE-Dextran transfection procedure but not with the calcium phosphate technique. A similar behavior was observed in Saccharomyces cerevisiae carrying wild type or truncated MMTV-lacZ reporters and expressing NFI-VP16. Reconstitution experiments suggest that the promoter lacking the HHR generates less stable nucleosomes, a fraction of which contain a more accessible NFI site. Recombinant NFI binds to nucleosomes assembled on this truncated promoter but not to nucleosomes encompassing the HRR. These results are compatible with the notion that transiently transfected MMTV promoters behave like their stably integrated counterparts, in that the HRR drives positioning of a nucleosome and mediates transcriptional repression by preventing access of NFI to its cognate site.
J Steroid Biochem Mol Biol 1996 Jan
PMID:The hormone responsive region of mouse mammary tumor virus positions a nucleosome and precludes access of nuclear factor I to the promoter. 864 14

The human herpes simplex virus type 1 (HSV-1) transactivator VP16 and its homolog from bovine herpes-virus 1 (BHV-1) can each recruit the human homeodomain protein Oct-1 into a transcriptional regulatory complex. Here, we show that these two Oct-1 coregulators possess similar, if not identical, homeodomain recognition properties but possess different virus-specific cis-regulatory specificities: the HSV-1 VP-16 protein activates transcription from the HSV-1 VP16 response element, and the BHV-1 VP16 protein activates transcription from the BHV-1 VP16 response element. A distinct 3-bp segment, the D segment, lying 3' of the canonical TAATGARAT motif (where R is a purine) in the VP16 response element is responsible for the differential cis element recognition and transcriptional activation by these two homeodomain coregulators. These results demonstrate how a single homeodomain protein can direct differential transcriptional regulation by selective association with homologous homeodomain coregulators.
Mol Cell Biol 1996 Jun
PMID:Differential control of transcription by homologous homeodomain coregulators. 864 8


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