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At least 163 records · Page 9Linked to original sources
PubMed2006

Genes regulated by estrogen in breast tumor cells in vitro are similarly regulated in vivo in tumor xenografts and human breast tumors.

BACKGROUND: Estrogen plays a central role in breast cancer pathogenesis. Although many studies have characterized the estrogen regulation of genes using in vitro cell culture models by global mRNA expression profiling, it is not clear whether these genes are similarly regulated in vivo or how they might be coordinately expressed in primary human tumors. RESULTS: We generated DNA microarray-based gene expression profiles from three estrogen receptor alpha (ERalpha)-positive breast cancer cell lines stimulated by 17beta-estradiol (E2) in vitro over a time course, as well as from MCF-7 cells grown as xenografts in ovariectomized athymic nude mice with E2 supplementation and after its withdrawal. When the patterns of genes regulated by E2 in vitro were compared to those obtained from xenografts, we found a remarkable overlap (over 40%) of genes regulated by E2 in both contexts. These patterns were compared to those obtained from published clinical data sets. We show that, as a group, E2-regulated genes from our preclinical models were co-expressed with ERalpha in a panel of ERalpha+ breast tumor mRNA profiles, when corrections were made for patient age, as well as with progesterone receptor. Furthermore, the E2-regulated genes were significantly enriched for transcriptional targets of the myc oncogene and were found to be coordinately expressed with Myc in human tumors. CONCLUSION: Our results provide significant validation of a widely used in vitro model of estrogen signaling as being pathologically relevant to breast cancers in vivo.

Age Factors↗
PubMed2002

Cell cycle-regulated gene expression in Arabidopsis.

Regulated gene expression is an important mechanism for controlling cell cycle progression in yeast and mammals, and genes involved in cell division-related processes often show transcriptional regulation dependent on cell cycle position. Analysis of cell cycle processes in plants has been hampered by the lack of synchronizable cell suspensions for Arabidopsis, and few cell cycle-regulated genes are known. Using a recently described synchrony system, we have analyzed RNA from sequential samples of Arabidopsis cells progressing through the cell cycle using Affymetrix Genearrays. We identify nearly 500 genes that robustly display significant fluctuation in expression, representing the first genomic analysis of cell cycle-regulated gene expression in any plant. In addition to the limited number of genes previously identified as cell cycle-regulated in plants, we also find specific patterns of regulation for genes known or suspected to be involved in signal transduction, transcriptional regulation, and hormonal regulation, including key genes of cytokinin response. Genes identified represent pathways that are cell cycle-regulated in other organisms and those involved in plant-specific processes. The range and number of cell cycle-regulated genes show the close integration of the plant cell cycle into a variety of cellular control and response pathways.

Aphidicolin↗
PubMed2003

Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1.

OBJECTIVE: The program of gene expression regulated by vascular endothelial growth factor (VEGF) remains poorly understood. The aim of this study was to identify VEGF-regulated genes in human umbilical vein endothelial cells. METHODS AND RESULTS: VEGF-regulated gene expression was analyzed by screening Affymetrix oligonucleotide arrays and quantitative, real-time, reverse transcription-polymerase chain reaction. The most strongly induced genes were the NR4A nuclear receptor family members Nur77, Nurr1, and Nor1 and the zinc-finger transcription factor Egr3. VEGF also induced rapid expression of Down syndrome candidate region 1, cyclooxygenase-2, tissue factor, stanniocalcin-1, the serine/threonine kinase Cot, and eps15 homology domain-containing protein. VEGF-induced NR4A family and Egr3 expression was blocked by a KDR inhibitor, and placental growth factor and basic fibroblast growth factor weakly increased expression of these genes. Induction of NR4A genes was mediated via intracellular Ca2+, protein kinase C- and calcineurin-dependent pathways. VEGF increased protein expression of Nurr1 and Nur77 and decreased Nur77 phosphorylation at the negative regulatory site serine 351. CONCLUSIONS: VEGF induces expression of NR4A nuclear receptors and Egr3 via KDR and KDR-mediated signaling mechanisms. The genes identified here are novel candidates as key early mediators of VEGF-induced endothelial functions.

Cells, Cultured↗
PubMed1996

Inducible gene expression and environmentally regulated genes in lactic acid bacteria.

Relatively recently, a number of genes and operons have been identified in lactic acid bacteria that are inducible and respond to environmental factors. Some of these genes/operons had been isolated and analysed because of their importance in the fermentation industry and, consequently, their transcription was studied and found to be regulatable. Examples are the lactose operon, the operon for nisin production, and genes in the proteolytic pathway of Lactococcus lactis, as well as xylose metabolism in Lactobacillus pentosus. Some other operons were specifically targetted with the aim to compare their mode of regulation with known regulatory mechanisms in other well-studied bacteria. These studies, dealing with the biosynthesis of histidine, tryptophan, and of the branched chain amino acids in L. lactis, have given new insights in gene regulation and in the occurrence of auxotrophy in these bacteria. Also, nucleotide sequence analyses of a number of lactococcal bacteriophages was recently initiated to, among other things, specifically learn more about regulation of the phage life cycle. Yet another approach in the analysis of regulated genes is the 'random' selection of genetic elements that respond to environmental stimuli and the first of such sequences from lactic acid bacteria have been identified and characterized. The potential of these regulatory elements in fundamental research and practical (industrial) applications will be discussed.

Amino Acids↗
PubMed2005

[Gene regulation and bioinformatics].

Gene regulation networks control differentiation and function of hundreds of cell types. Dysfunctions of transcription factors, which are key elements in the regulation pathways, are involved in numerous pathologies. The recent development of genomics technologies allows the study of gene regulation mechanisms and help us understand their impact on the cells. Bioinformatic tools are needed to fully exploit data obtained by genomics approaches. Thus, bioinformatics play an essential role in the characterisation of the transcription factors binding sites and their target genes. In this review we will introduce the main breakthroughs in bioinformatics area for the comprehension of regulation mechanisms. We will insist on i) the approaches "with a priori" for the genome annotation based on known transcription factors binding sites, ii) the approaches "without a priori" for the discovery of new binding sites and iii) the functional annotation of the target genes of those transcription factors. Finally, we will present recent examples of the fruitful use of in silico studies for the comprehension of regulation mechanisms and of the consequences of their dysfunction.

Algorithms↗
PubMed2005

Characterization and developmental gene regulation of a large gene family encoding amastin surface proteins in Leishmania spp.

The ability of Leishmania amastigotes to survive within the drastic environmental changes encountered in the phagolysosomes of mammalian macrophages is heavily dependent on the developmental regulation of a variety of genes. The identification of genes that are expressed preferentially in the mammalian stage of the parasite should increase our understanding of the molecular mechanisms regulating stage-specific gene expression and of the determinants that control its intracellular survival and contribute to its pathogenesis. We report here detailed sequence characterization and structural organization of the amastin gene family in Leishmania major and Leishmania infantum and the study of their developmental gene regulation throughout the parasite's life cycle. Amastin surface proteins represent the largest developmentally regulated gene family reported so far in Leishmania comprising up to 45 members. All the members of the amastin gene family in both Leishmania and Trypanosoma species share a similar structural organization and contain a highly conserved 11 amino acid extracellular domain, which is unique to amastin proteins. The majority of the amastin gene homologs are specifically expressed in the amastigote stage of the parasite. Three distinct RNA elements were identified in the 3'-untranslated regions (3'UTR) of the amastin transcripts. The majority of these transcripts contain a conserved 450 nt cis-acting 3'UTR element shown previously to regulate stage-specific gene expression at the level of translation, which suggests that several amastin homologs may be regulated by a similar mechanism of translational control inside the macrophage. These findings further highlight the unique features of gene expression control in Leishmania.

3' Untranslated Regions↗
PubMed1991

The ecdysone-induced puffing cascade in Drosophila salivary glands: a Broad-Complex early gene regulates intermolt and late gene transcription.

The steroid hormone 20-OH ecdysone triggers a classic and well-defined program of chromosome puffing that is assumed to reflect changes in transcriptional activity in Drosophila salivary glands. Mutations in each of four Broad-Complex locus (BR-C) complementation groups were analyzed for their effects on the expression of other genes that reside in several major salivary gland puffs. RNA blot analysis showed that the rbp function of the BR-C is required for the transcription of six genes in the 71E late puff and is the first demonstration that an ecdysone-induced early gene controls the transcription of late genes within the puffing cascade. In addition, the rbp function is required for the transcription of four intermolt genes (Sgs-3, Sgs-4, Sgs-5 and 71E gene VII). Mutations in the broad, l(1)2Bc and l(1)2Bd functions of the BR-C had no effect on the expression of the genes examined. We propose that the BR-C functions to control transcription at many other salivary gland loci at the beginning of metamorphosis.

Animals↗
PubMed2002

Artificial mammalian gene regulation networks-novel approaches for gene therapy and bioengineering.

Recently developed strategies for targeted molecular interventions in mammalian cells have created novel opportunities in biotechnological and biomedical research with huge economic and therapeutic impact: the design of mammalian cells with desired phenotypes for biopharmaceutical manufacturing, tissue engineering and gene therapy. These advances have been enabled by constructing artificial gene regulation systems with control modalities similar to those evolved in key regulatory networks of mammalian cells. This review highlights recurring cellular regulation strategies and artificial gene regulation technology currently in use for rational reprogramming of cellular key events including metabolism, growth, differentiation and cell death to achieve sophisticated bioprocess and therapeutic goals.

Animals↗
PubMed2000

A method for direct cloning of fur-regulated genes: identification of seven new fur-regulated loci in Escherichia coli.

A strain that allows the cloning of Fur-regulated loci was constructed. The strain, named FUR-SEL1, contains a chromosomal fhuA'-'cat transcriptional fusion that is expressed from the Fur-regulated promoter, fhuA(p). Therefore, Fur boxes introduced on a multicopy plasmid can cause derepression of the fusion by titrating the Fur repressor and thereby confer chloramphenicol resistance, which can be used as a selectable phenotype for cloning Fur-regulated loci. However, a number of additional mutations had to be introduced before FUR-SEL1 could be used for cloning Fur-regulated genes. The principal approach consisted of introducing a leaky fur mutation that ensures a more than 10(6)-fold increase in chloramphenicol resistance for FUR-SEL1 transformants carrying FUR-box-containing plasmids. To verify that the cloning procedure selects Fur-regulated genes, 10 recombinant plasmids chosen at random among the ones selected with FUR-SEL1 were analysed by FURTA (Fur-titration assay), a method for identification of Fur-regulated genes. In addition, the nucleotide sequences of their chromosomal inserts were determined. Besides known Fur-regulated genes, seven Escherichia coli loci which have not previously been shown to be Fur regulated were found, including the pgmA and nrdHIEF genes, predicted ORF yhhY and four promoters identified first in this study. Three of the promoters preceded the nohA gene, and ORFs ygaC and yhhX. The fourth was located upstream of orf78 predicted in this work. The regulation of the promoter activities by iron and the involvement of Fur in this regulation were shown. Employing FUR-SEL1 for cloning Fur-regulated loci from other enterobacteria is discussed.

Bacterial Proteins↗
PubMed1983

Two RNA polymerase sigma factors from Bacillus subtilis discriminate between overlapping promoters for a developmentally regulated gene.

A developmentally regulated gene (spoVG) from the spore-forming bacterium Bacillus subtilis is expressed from two overlapping promoters, which direct transcription initiating from sites separated by 10 base pairs. Utilization of the upstream promoter is determined by an RNA polymerase sigma factor of molecular weight 37,000 (sigma 37). We report the isolation of a 32,000-molecular weight species of sigma factor (sigma 32), which exclusively dictates transcription initiation from the downstream promoter, and suggest a model for the way in which sigma-specific recognition sequences are intermeshed within the spoVG transcription initiation region.

Bacillus subtilis↗
PubMed2004

Steroid degradation gene cluster of Comamonas testosteroni consisting of 18 putative genes from meta-cleavage enzyme gene tesB to regulator gene tesR.

Steroid degradation genes of Comamonas testosteroni TA441 are encoded in at least two gene clusters: one containing the meta-cleavage enzyme gene tesB and ORF1, 2, 3; and another consisting of ORF18, 17, tesI, H, A2, and tesA1, D, E, F, G (tesA2 to ORF18 and tesA1 to tesG are encoded in opposite directions). Analysis of transposon mutants with low steroid degradation revealed 13 ORFs and a gene (ORF4, 5, 21, 22, 23, 25, 26, 27, 28, 30, 31, 32, 33, and tesR) involved in steroid degradation in the downstream region of ORF3. TesR, which is almost identical to that of TeiR, a positive regulator of Delta1-dehydrogenase (corresponds to TesH in TA441) and 3alpha-dehydrogenase (currently not identified in TA441), in C. testosteroni ATCC11996 (Pruneda-Paz, 2004), was shown to be necessary for induction of the steroid degradation gene clusters identified in TA441, tesB to tesR, tesA1 to tesG, and tesA2 to ORF18. At least some of the ORFs from ORF3 to ORF33 were suggested to be involved in 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid degradation.

Bacterial Proteins↗
PubMed2006

Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression.

The plant Withania somnifera Dunal (Ashwagandha), also known as Indian ginseng, is widely used in the Ayurvedic system of medicine to treat tumors, inflammation, arthritis, asthma, and hypertension. Chemical investigation of the roots and leaves of this plant has yielded bioactive withanolides. Earlier studies showed that withanolides inhibit cyclooxygenase enzymes, lipid peroxidation, and proliferation of tumor cells. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and inflammation are regulated by activation of nuclear factor-kappaB (NF-kappaB), we hypothesized that the activity of withanolides is mediated through modulation of NF-kappaB activation. For this report, we investigated the effect of the withanolide on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We found that withanolides suppressed NF-kappaB activation induced by a variety of inflammatory and carcinogenic agents, including tumor necrosis factor (TNF), interleukin-1beta, doxorubicin, and cigarette smoke condensate. Suppression was not cell type specific, as both inducible and constitutive NF-kappaB activation was blocked by withanolides. The suppression occurred through the inhibition of inhibitory subunit of IkappaB alpha kinase activation, IkappaB alpha phosphorylation, IkappaB alpha degradation, p65 phosphorylation, and subsequent p65 nuclear translocation. NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR-associated death domain, TNFR-associated factor 2, and IkappaB alpha kinase was also suppressed. Consequently, withanolide suppressed the expression of TNF-induced NF-kappaB-regulated antiapoptotic (inhibitor of apoptosis protein 1, Bfl-1/A1, and FADD-like interleukin-1beta-converting enzyme-inhibitory protein) and metastatic (cyclooxygenase-2 and intercellular adhesion molecule-1) gene products, enhanced the apoptosis induced by TNF and chemotherapeutic agents, and suppressed cellular TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis. Overall, our results indicate that withanolides inhibit activation of NF-kappaB and NF-kappaB-regulated gene expression, which may explain the ability of withanolides to enhance apoptosis and inhibit invasion and osteoclastogenesis.

Animals↗
PubMed2003

Zinc-finger protein-targeted gene regulation: genomewide single-gene specificity.

Zinc-finger protein transcription factors (ZFP TFs) can be designed to control the expression of any desired target gene, and thus provide potential therapeutic tools for the study and treatment of disease. Here we report that a ZFP TF can repress target gene expression with single-gene specificity within the human genome. A ZFP TF repressor that binds an 18-bp recognition sequence within the promoter of the endogenous CHK2 gene gives a >10-fold reduction in CHK2 mRNA and protein. This level of repression was sufficient to generate a functional phenotype, as demonstrated by the loss of DNA damage-induced CHK2-dependent p53 phosphorylation. We determined the specificity of repression by using DNA microarrays and found that the ZFP TF repressed a single gene (CHK2) within the monitored genome in two different cell types. These data demonstrate the utility of ZFP TFs as precise tools for target validation, and highlight their potential as clinical therapeutics.

Base Sequence↗
PubMed1999

Antisense expression of the CK2 alpha-subunit gene in Arabidopsis. Effects on light-regulated gene expression and plant growth.

The protein kinase CK2 (formerly casein kinase II) is thought to be involved in light-regulated gene expression in plants because of its ability to phosphorylate transcription factors that bind to the promoter regions of light-regulated genes in vitro. To address this possibility in vivo and to learn more about the potential physiological roles of CK2 in plants, we transformed Arabidopsis with an antisense construct of the CK2 alpha-subunit gene and investigated both morphological and molecular phenotypes. Antisense transformants had a smaller adult leaf size and showed increased expression of chs in darkness and of cab and rbcS after red-light treatment. The latter molecular phenotype implied that CK2 might serve as one of several negative and quantitative effectors in light-regulated gene expression. The possible mechanism of CK2 action and its involvement in the phytochrome signal transduction pathway are discussed.

Arabidopsis↗
PubMed2000

A novel integron in Salmonella enterica serovar Enteritidis, carrying the bla(DHA-1) gene and its regulator gene ampR, originated from Morganella morganii.

The genetic organization of the gene coding for DHA-1 and the corresponding ampR gene was determined by PCR mapping. These genes have been mobilized from the Morganella morganii chromosome and inserted into a complex sulI-type integron, similar to In6 and In7. However, they are not themselves mobile cassettes. This integron probably includes a specific site for recombination allowing the mobilization of diverse resistance genes, as observed for bla(CMY-1) and bla(MOX-1).

Bacterial Proteins↗
PubMed2000

Allelic differences in bovine kappa-CN gene which may regulate gene expression.

The most common kappa casein (kappa-CN) variants, kappa-CN A and kappa-CN B, are synthesised differentially in the lactating mammary gland of heterozygous animals (kappa-CN AB). In this study we evaluated several approaches for quantification of allele specific mRNA transcripts. The most consistent results were obtained using allele specific RT-PCR and capillary electrophoresis. On average, 13.4% more allele B specific than A specific transcripts were found. DNA sequencing of the proximal promoter region in several homozygous animals (kappa-CN AA, BB, EE) did not reveal any allele specific polymorphisms. Using the EMSA and DNase I footprinting we confirmed functional binding sites for three transcription factors (AP-2, NF1 and MGF) within the kappa-CN proximal promoter region. Sequence analysis of the 3'-UTR of the kappa-CN gene revealed seven allele specific sites. Two of these allelic differences were close to previously identified 3'-end regulatory sequences. In addition, allele specific differences in length between mRNAs of both variants were found. The two later findings suggest a possible post translational control determining content differences of kappa-CN in milk.

3' Untranslated Regions↗
PubMed1983

Purification of the bacteriophage lambda late gene regulator encoded by gene Q.

The product of bacteriophage lambda gene Q is a transcription antiterminator that activates phage late gene expression. We report a method to purify the lambda Q protein to near homogeneity. We have followed during purification both activity of Q protein to provoke in vitro synthesis of the lambda late protein endolysin in the DNA-dependent protein-synthesizing system, and radioactivity in a polypeptide that we show by genetic criteria to be lambda Q. These co-purify throughout the procedure.

Bacteriophage lambda↗
PubMed2001

The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression.

Regulation of NF-kappaB transactivation function is controlled at several levels, including interactions with coactivator proteins. Here we show that the transactivation function of NF-kappaB is also regulated through interaction of the p65 (RelA) subunit with histone deacetylase (HDAC) corepressor proteins. Our results show that inhibition of HDAC activity with trichostatin A (TSA) results in an increase in both basal and induced expression of an integrated NF-kappaB-dependent reporter gene. Chromatin immunoprecipitation (ChIP) assays show that TSA treatment causes hyperacetylation of the wild-type integrated NF-kappaB-dependent reporter but not of a mutant version in which the NF-kappaB binding sites were mutated. Expression of HDAC1 and HDAC2 repressed tumor necrosis factor (TNF)-induced NF-kappaB-dependent gene expression. Consistent with this, we show that HDAC1 and HDAC2 target NF-kappaB through a direct association of HDAC1 with the Rel homology domain of p65. HDAC2 does not interact with NF-kappaB directly but can regulate NF-kappaB activity through its association with HDAC1. Finally, we show that inhibition of HDAC activity with TSA causes an increase in both basal and TNF-induced expression of the NF-kappaB-regulated interleukin-8 (IL-8) gene. Similar to the wild-type integrated NF-kappaB-dependent reporter, ChIP assays showed that TSA treatment resulted in hyperacetylation of the IL-8 promoter. These data indicate that the transactivation function of NF-kappaB is regulated in part through its association with HDAC corepressor proteins. Moreover, it suggests that the association of NF-kappaB with the HDAC1 and HDAC2 corepressor proteins functions to repress expression of NF-kappaB-regulated genes as well as to control the induced level of expression of these genes.

3T3 Cells↗