Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have cloned and characterized a mouse cDNA coding for LFB3, a DNA binding protein containing an extra-large homeodomain. The first 315 amino acids of LFB3 are highly homologous to the DNA binding domain of LFB1, a regulatory protein involved in the expression of several liver-specific genes. LFB3 is a transcriptional activator which binds to DNA as a dimer and forms heterodimers with LFB1 both in vitro and in vivo. However, LFB3 expression seems not to be directly correlated with the liver-specific phenotype, since it is detected in dedifferentiated hepatoma cell lines which express neither LFB1 nor several liver-specific genes. LFB3 expression starts before that of LFB1 during mouse and rat development, and is strongly increased upon retinoic acid induced differentiation of F9 embryonic carcinoma cells. LFB3 and LFB1 are expressed in the epithelial component of many organs of endodermal and mesodermal origin, suggesting that they may play a more general role associated with the differentiation of specialized epithelia.
 ...
PMID:LFB3, a heterodimer-forming homeoprotein of the LFB1 family, is expressed in specialized epithelia. 167 25

The HBx protein of hepatitis B virus (HBV) is a transcriptional activator that is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. Recently, we and others have shown that HBx stimulates the Ras-Raf-MAP kinase cascade, which leads to enhanced cell proliferation and the activation of transcription factors AP-1 and NF-kappa B. Other studies have shown that HBx can activate transcription by interacting directly with nuclear components of the transcription machinery. Therefore we examined the basis for the different reported activities of HBx. Here, we show that HBx is a complex protein, displaying independent activities in different intracellular locations. The intracellular distribution of HBx protein was first investigated using scanning confocal laser immunomicroscopy and by genetic studies. Our work has established that HBx expressed in cultured cells is found authentically in both the cytoplasm and the nucleus. HBx is not strongly associated with any intracellular structures, but some preferential accumulation was observed near the cell surface. Next, HBx variants were constructed containing a functional or mutant nuclear localization sequence. We show that when HBx is engineered to relocate exclusively to the nucleus, it no longer activates the Ras-Raf-MAP kinase cascade, nor does it activate transcription factors AP-1 and NF-kappa B. Surprisingly, nuclear HBx fully retains the ability to stimulate HBV enhancer I, which is activated independently of the Ras and protein kinase C pathways. Therefore HBx protein stimulates signal transduction pathways in the cytoplasm and transactivates transcription elements in the nucleus. Furthermore, SV40 T antigen is shown to induce the nuclear sequestration of HBx protein and to block its activation of NF-kappa B, demonstrating that HBx is regulated by proteins that alter its intracellular distribution. The conflicting functions of HBx protein in viral infection and possibly carcinoma may involve the regulation of its differential distribution in the cell.
 ...
PMID:The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. 758 4

The retinoblastoma tumor suppressor protein (RB) binds several cellular proteins involved in cell cycle progression. Using the yeast two-hybrid system, we found that RB bound specifically to the protein BRG1. BRG1 shares extensive sequence similarity to Drosophila brahma, an activator of homeotic gene expression, and the yeast transcriptional activator SNF2/SW12. BRG1 contains an RB-binding motif found in viral oncoproteins and bound to the A/B pocket and the hypophosphorylated form of RB. BRG1 did not bind RB in viral oncoprotein-transformed cells. Coimmunoprecipitation experiments suggested BRG1 associates with the RB family in vivo. In the human carcinoma cell line SW13, BRG1 exhibited tumor suppressor activity by inducing formation of flat, growth-arrested cells. This activity depended on the ability of BRG1 to cooperate and complex with RB, as both an RB-nonbinding mutant of BRG1 and the sequestration of RB by adenovirus E1A protein abolished flat cell formation.
 ...
PMID:The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. 792 70

Cells with divergent mutant alleles of the p53 gene have different biological and biochemical properties in vitro. Increasing evidence indicates that p53 is a transcriptional activator, and recently, high affinity DNA binding sites for p53 have been identified. The purpose of this study was to determine in vivo, the effect that various mutant p53 proteins have on their ability to mediate transactivation and to bind specifically to DNA. Either a p53 responsive or control reporter gene was transfected into 18 human carcinoma cell lines, having various p53 mutations, either with or without a wild-type p53 expression vector. The CAT activity and DNA gel retardation were studied to measure transactivation and DNA binding by these endogenous p53s. As expected, the endogenously produced wild-type p53 binds to DNA binding sequences and can transactivate a reporter construct containing a p53 high affinity DNA binding site. Four of five cell lines with homozygous p53 mutations at codon 273 (273His), contained p53 which had the ability to bind to p53 DNA binding sequences and transactivate. In contrast, all the homozygous, non-codon 273 mutant p53s (156Pro, 175His, 223Leu, 248Gln, 248Trp, 280Lys) present in the other cell lines had no transactivating ability. These findings suggest that the biology of cancers with mutations at codon 273 may be different than those with p53 mutations at other sites. The p53 from WRO, a thyroid carcinoma cell line with p53 mutation at codon 223 (223Leu), was able to bind p53 DNA recognition sequences, but was unable to transactivate. Interestingly, in a vulvar carcinoma cell line (A431) with a p53 mutation at codon 273 (273His), the p53 was unable to transactivate and gave an aberrant band on gel retardation. Both CEM and SK-UT-1, which have compound heterozygous mutations at codons 175/248 (175His/248His), produced p53 which can complex with DNA, as well as transactivate. In contrast, the p53 in cell lines with either homozygous 175His or 248His p53 mutations, were unable either to transactivate or bind to the p53 response element. A cell line (NPA) heterozygous for 266Glu p53 mutation, was able to efficiently transactivate a reporter containing a p53 DNA binding site, therefore showing no evidence of a dominant negative effect of the endogenous p53 mutant allele. In summary, this in vivo study further supports the idea that different p53 mutant alleles have various properties which may affect their function.
 ...
PMID:Transactivational and DNA binding abilities of endogenous p53 in p53 mutant cell lines. 820 36

p53 is a nuclear phosphoprotein whose function is classified as tumor suppression. Studies have shown that p53 functions by binding to p53 DNA recognition sequences and regulates transcription of growth-regulatory genes. Various p53 recognition sequences have recently been identified. pOST2 contained two copies of a palindromic high-affinity DNA-binding sequence for p53; the other p53 recognition sequences included p53-binding fragments found in the human ribosomal gene cluster (pRGC) region and in the murine muscle creatine kinase promoter (pMCK). The purpose of this study was to compare the abilities of various p53 recognition sequences to mediate transcription in the presence of endogenously produced wild-type (wt) or mutant p53. Three p53-responsive chloramphenicol acetyltransferase (CAT) reporter constructs (pOST2, pRGC, and pMCK) that contain one or two copies of p53 recognition sequences upstream of a herpes thymidine kinase (TK) promoter and CAT reporter cDNA were constructed. Either a p53-responsive gene or a control reporter gene was transfected into human carcinoma cell lines (having various p53 mutations) either with or without a wt or mutant p53 expression vector. CAT activity was assayed to measure transactivation through the various p53-responsive elements. We showed that pOST2 had a greater ability to mediate transactivation by p53 than either pRGC or pMCK. p53 with a mutation at either codon 175 or 248 was unable to transactivate a reporter gene with pOST2, pRGC, or pMCK. We found it interesting that pOST2, but not pRGC or pMCK, was able to mediate transactivation in cell lines that produce codon 273-mutant p53. These findings suggest that various sensitivities of the different p53-responsive elements to specific mutant and wt p53s may be an important factor in the role of p53 as a transcriptional activator both under normal physiological conditions and during carcinogenesis.
 ...
PMID:p53 transactivation through various p53-responsive elements. 864 24

Treatment of T47-D human breast carcinoma cells with recombinant prolactin (rhPRL) induced a concentration- and time-dependent increase in the phosphotyrosine content of JAK2. rhPRL also stimulated JAK2 tyrosine phosphorylation more weakly in three other breast carcinoma lines, MCF-7, ZR-75-1 and MDA-MB-231. Furthermore it stimulated tyrosine phosphorylation of two isoforms of the transcriptional activator STAT5, STAT5a and STAT5b. Surprisingly, rhPRL treatment of T47-D cells also stimulated tyrosine phosphorylation of focal adhesion kinase (FAK), as determined by immunoprecipitation with anti-phosphotyrosine antibody followed by immunoblotting with a specific FAK antibody. The effect of rhPRL was rapid and concentration-dependent, being maximal at 5 ng/ml. At rhPRL concentrations above 25 ng/ml, FAK tyrosine phosphorylation declined but remained above control levels at 100 ng/ml. rhPRL also stimulated paxillin tyrosine phosphorylation in T47-D cells with similar concentration- and time-dependence. In a second human breast carcinoma cell line, MCF-7, rhPRL produced very similar effects on FAK and paxillin tyrosine phosphorylation. These findings identify a new protein tyrosine kinase pathway in the action of the lactogenic hormone rhPRL and represent the first report that a hormone acting through a member of the haemopoietin receptor superfamily can regulate the FAK/paxillin pathway.
 ...
PMID:Prolactin stimulates the JAK2 and focal adhesion kinase pathways in human breast carcinoma T47-D cells. 916 61

Replication of the Epstein-Barr virus (EBV) genome within latently infected cells is dependent on the EBV EBNA-1 protein. The objective of this study was to identify transcriptional regulatory proteins that mediate EBNA-1 expression via the viral promoter Qp, which is active in EBV-associated tumors such as Burkitt lymphoma and nasopharyngeal carcinoma. Results of a yeast one-hybrid screen suggested that a subset of the interferon regulatory factor (IRF) family may regulate EBNA-1 transcription by targeting an essential cis-regulatory element of Qp, QRE-2. Further investigation indicated that the transcriptional activator IRF-1 and the closely related IRF-2, a repressor of interferon-induced gene expression, are both capable of activating Qp. However, the major QRE-2-specific binding activity detected within extracts of Burkitt lymphoma cells was attributed to IRF-2, suggesting that interferon-independent activation of Qp is largely mediated by IRF-2 in these cells. We observed no effect of gamma interferon on Qp activity in transfection assays, whereas we observed a moderate but significant repression of Qp activity in response to alpha interferon, possibly mediated by either the interferon consensus sequence binding protein or IRF-7, a novel alpha interferon-inducible factor identified in this study. Since expression of IRF-1 and IRF-2 is increased in response to interferons, the Qp activity observed in the presence of interferon likely represented an equilibrium between IRF factors that activate and those that repress gene expression in response to interferon. Thus, by usurping both IRF-1 and its transcriptional antagonist IRF-2 to activate Qp, EBV has evolved not only a mechanism to constitutively express EBNA-1 but also one which may sustain EBNA-1 expression in the face of the antiviral effects of interferon.
 ...
PMID:Interferon-independent and -induced regulation of Epstein-Barr virus EBNA-1 gene transcription in Burkitt lymphoma. 926 15

In humans, the biological response to progesterone is mediated by two distinct forms of the progesterone receptor (human (h) PR-A, 94 kDa and hPR-B, 114 kDa). These two isoforms are transcribed from distinct estrogen-inducible promoters within a single copy PR gene; the only difference between them is that the first 164 amino acids of hPR-B (B-upstream sequence) are absent in hPR-A. In most cell lines such as MCF-7 (human breast cancer cells), CV-1 (monkey kidney fibroblasts), and HeLa (human cervical carcinoma cells), hPR-A functions as a transcriptional repressor, whereas hPR-B functions as a transcriptional activator of progesterone-responsive genes. Interestingly, in these cell contexts, hPR-A also acts as a trans-dominant repressor of the transcriptional activity of other steroid hormone receptors. In contrast to hPR-A, which functions predominantly as a ligand-dependent transcriptional repressor, we show in this study that the A isoform of the chicken PR (cPR-A) lacks this trans-dominant repressor function and is a transcriptional activator in all contexts examined. By constructing chimeras between the N-terminal domains of the chicken and human PR, we mapped the trans-dominant repressor function of hPR-A to the first 140 amino acids of the protein. Notably, when this 140-amino acid "repressor" domain is placed onto chicken PR-A, the activity of the latter changes from a transcriptional activator to a repressor. Interestingly, however, this "repressor domain" is necessary, but not sufficient, for trans-repression as it is inactive when it is tethered to a heterologous protein. This suggests that the trans-repression function is comprised not only of the repressor domain of hPR-A but also requires the context of the receptor to function. The identification of a discrete inhibitory region within hPR-A which is transferable to another receptor implies that this region interacts with a set of transcription factors or adaptors that are distinct from those recognized by hPR-B, the identification of which will be required to define the mechanism by which hPR-A modulates steroid hormone receptor transcriptional activity. Thus, although chickens and humans both produce two very similar forms of the progesterone receptor, it is clear from these studies that the mechanism of action of progesterone in these two systems is quite different.
 ...
PMID:Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. 940 67

We have applied the mRNA differential display method to compare and analyze mRNAs prepared from five normal nasopharyngeal epithelial cell cultures and five nasopharyngeal carcinoma cell lines. A total of 24 differential display experiments was performed using different combinations of PCR primers. Sixty-nine cDNA fragments differentially expressed in either normal or malignant nasopharyngeal epithelial cells were identified. Subsequent cloning and sequencing of these differentially expressed cDNA fragments resulted in the identification of seventeen distinct sequences. Seven of these sequences were shown to be novel cDNA sequences not previously reported. Ten of the remaining cDNA fragments showed sequence homology to previously reported genes. Differential expression of four of these seventeen cDNA fragments in normal nasopharyngeal epithelial cells was confirmed by reverse Northern hybridization. One of these cloned cDNA fragments is a novel cDNA sequence while the other three matched to previously reported cDNA sequences involved in cell growth and migration. Homologous sequences identified to be differentially expressed in normal nasopharyngeal epithelial cells in this study are: human 26 kDa cell surface protein (TAPA-1) mRNA, NF-E2 like basic leucine zipper transcriptional activator and the human bullous pemphigoid antigen. The mRNA differential display is a useful tool to identify candidate genes involved in the pathogenesis of nasopharyngeal carcinoma.
 ...
PMID:Identification of genes differentially expressed in nasopharyngeal carcinoma by messenger RNA differential display. 962 7

Beta-catenin forms complexes with Tcf and Lef-1 and functions as a transcriptional activator downstream of the Wnt signaling pathway. Activation of the pathway by stabilization of beta-catenin has been shown to be important in the development of colorectal carcinoma, which is mainly caused by inactivating mutations of the adenomatous polyposis coli tumor suppressor gene or by activating mutations in exon 3 of the beta-catenin gene. Here, we analyzed mutations in exon 3 of the beta-catenin gene in endometrial carcinoma cases in which loss of heterozygosity at the adenomatous polyposis coli tumor suppressor gene locus has been rarely reported. We found that 10 of 76 cases had beta-catenin gene mutations. All mutations identified were single-base missense mutations on serine/threonine residues (codons 33, 37, 41, and 45), altering the glycogen synthase kinase-3beta phosphorylation consensus motif, which participates in the degradation of beta-catenin. To determine whether these beta-catenin mutations actually led to stabilization of this protein, expression of beta-catenin was analyzed immunohistochemically, and 9 of 10 cases with the beta-catenin mutation and 20 of 66 cases without it showed accumulation of beta-catenin in the cytoplasm and/or nucleus. In total, 38% of cases showed accumulation of beta-catenin. These data indicate that stabilization of beta-catenin due to mutations in exon 3 of the beta-catenin gene and other mechanisms may have an important role in development of endometrial carcinomas.
 ...
PMID:Beta-catenin mutation in carcinoma of the uterine endometrium. 972 53


1 2 3 4 5 6 Next >>