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At least 937 records · Page 52Linked to original sources
PubMed2005

Differential regulation of fatty acid elongation enzymes in brown adipocytes implies a unique role for Elovl3 during increased fatty acid oxidation.

The expression of the Elovl3 gene, which belongs to the Elovl gene family coding for microsomal enzymes involved in very long-chain fatty acid (VLCFA) elongation, is dramatically increased in mouse brown adipose tissue upon cold stimulation. In the present study, we show that the cold-induced Elovl3 expression is under the control of peroxisome proliferator-activated receptor-alpha (PPARalpha) and that this regulation is part of a fundamental divergence in the regulation of expression for the different members of the Elovl gene family. In cultured brown adipocytes, a mixture of norepinephrine, dexamethasone, and the PPARalpha ligand Wy-14643, which rendered the adipocytes a high oxidative state, was required for substantial induction of Elovl3 expression, whereas the same treatment suppressed Elovl1 mRNA levels. The nuclear liver X receptor (LXR) has been implicated in the control of fatty acid synthesis and subsequent lipogenic processes in several tissues. This regulation is also exerted in part by sterol regulatory element-binding protein (SREBP-1), which is a target gene of LXR. We found that stimulation of Elovl3 expression was independent of LXR and SREBP-1 activation. In addition, exposure to the LXR agonist TO-901317 increased nuclear abundance of LXR and mature SREBP-1 as well as expression of the elongases Lce and Elovl1 in a lipogenic fashion but repressed Elovl3 expression. A functional consequence of this was seen on the level of esterified saturated fatty acids, such as C22:0, which was coupled to Elovl3 expression. These data demonstrate differential transcriptional regulation and concomitantly different functional roles for fatty acid elongases in lipid metabolism of brown adipocytes, which reflects the metabolic status of the cells.

Acetyltransferases↗
PubMed1991

The bidirectional promoter of the divergently transcribed mouse Surf-1 and Surf-2 genes.

The ubiquitously expressed mouse Surf-1 and Surf-2 genes are divergently transcribed, and their heterogeneous start sites are separated by up to a maximum of only 73 bp. By using in vitro DNase I, dimethyl sulfate methylation, and gel retardation assays, we have identified five putative promoter control elements between and around the Surf-1 and Surf-2 start sites. The effects of each site on the regulation of Surf-1 and Surf-2 transcription have been studied in vivo, and four sites were found to be functional promoter elements. A novel binding site is required for efficient use of the intermediate but not the major start site of Surf-1. Three elements function in a bidirectional manner and are shared for efficient and accurate expression of both Surf-1 and Surf-2. One is an UEF (USF, MLTF) binding site which had a small effect on the use of the intermediate start sites of Surf-1 and also affected the major start sites of Surf-2. Another has sequence homology to the RPG alpha binding site associated with some ribosomal protein gene promoters and is required for efficient expression of the major but not intermediate start sites of Surf-1 and all start sites of Surf-2. The third, an RPG alpha-like site, is used for all start sites of both Surf-1 and Surf-2. Dissection of this cellular promoter region showed that different binding sites affect the use of different start sites and revealed a complex interaction between multiple elements that constitute a bona fide bidirectional promoter.

Animals↗
PubMed1993

Cell type- and stage-specific expression of the CD20/B1 antigen correlates with the activity of a diverged octamer DNA motif present in its promoter.

The CD20(B1) gene encodes a B cell-specific protein involved in the regulation of human B cell proliferation and differentiation. Studies with 5' deletion CD20 promoter-CAT constructs have previously revealed two regions of the promoter between bases -186 and -280 and between bases -280 and -454 which contained positive regulatory elements. In this study we identified a sequence element present in the most proximal region located between bases -214 and -201, TTCTTCTAATTAA, which is important in the high constitutive expression of CD20 in mature B cells and the induction of CD20 in pre-B cells. This sequence element was referred to as the BAT box and its deletion significantly reduced the activity of a CD20 promoter-CAT construct in B cells. Mobility shift assays with various mutant probes and B cell nuclear extracts demonstrated that the core sequence TAAT was essential for binding to this site. Cross competition experiments with an octamer sequence from the Ig heavy chain promoter, the BAT box, and a TA-rich sequence present in the CD21 promoter revealed that all three sequences bound the same nuclear proteins suggesting that the BAT box binding proteins were Oct-1 and Oct-2. Southwestern blotting and UV cross-linking studies confirmed that the BAT box binding proteins were Oct-1 and Oct-2. The affinity of the BAT box binding proteins for the BAT box was approximately 25-fold less than for the octamer sequence and the BAT box binding proteins dissociated from the BAT box 10-fold more rapidly than from the octamer sequence. Despite this lower affinity, a trimer of the BAT box sequence was as efficiently transactivated by an Oct-2 expression vector as was a trimer of the octamer sequence in HeLa cells. The BAT box and Oct-2 were also implicated in the induction of CD20 in the pre-B cell line, PB-697, via phorbol esters. The induction of CD20 mRNA was temporally associated with induction of Oct-2 mRNA and a BAT box-deleted CD20-CAT construct, in contrast to the wild type, was poorly induced by phorbol esters. Together these results suggest that the BAT box binding proteins are important in the B cell specific expression of CD20 and perhaps CD21.

Antigens, CD↗
PubMed2006

Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes.

Most genes are conserved in mammals, but certain gene families have acquired large numbers of lineage-specific loci through repeated rounds of gene duplication, divergence, and loss that have continued in each mammalian group. One such family encodes KRAB-zinc finger (KRAB-ZNF) proteins, which function as transcriptional repressors. One particular subfamily of KRAB-ZNF genes, including ZNF91, has expanded specifically in primates to comprise more than 110 loci in the human genome. Genes of the ZNF91 subfamily reside in large gene clusters near centromeric regions of human chromosomes 19 and 7 with smaller clusters or isolated copies in other locations. Phylogenetic analysis indicates that many of these genes arose before the split between the New and Old World monkeys, but the ZNF91 subfamily has continued to expand and diversify throughout the evolution of apes and humans. Paralogous loci are distinguished by divergence within their zinc finger arrays, indicating selection for proteins with different regulatory targets. In addition, many loci produce multiple alternatively spliced transcripts encoding proteins that may serve separate and perhaps even opposing regulatory roles because of the modular motif structure of KRAB-ZNF genes. The tissue-specific expression patterns and rapid structural divergence of ZNF91 subfamily genes suggest a role in determining gene expression differences between species and the evolution of novel primate traits.

Animals↗
PubMed2001

Cloning of mouse BMAL2 and its daily expression profile in the suprachiasmatic nucleus: a remarkable acceleration of Bmal2 sequence divergence after Bmal gene duplication.

Brain-Muscle-Arnt-Like-protein 2 (BMAL2; Arnt4) (aryl hydrocarbon receptor nuclear translocator) is a recently identified basic Helix-Loop-Helix-Per-Arnt-Sim (bHLH-PAS) transcription factor, which contributes to a positive regulation of autoregulatory feedback loop in vertebrate circadian clock systems. In this study, we cloned cDNAs encoding mouse and rat BMAL2 (mBMAL2 and rBMAL2) from mouse midbrain and rat-1 fibroblast cells, respectively. A phylogenetic analysis strongly suggested that vertebrate Bmal1 and Bmal2 genes were generated by a single gene duplication of an ancestral Bmal gene, a vertebrate ortholog of dCyc gene, and that 'BMAL2's putatively termed so far are orthologous. Interestingly, BMAL2 proteins have diverged about 20-fold more rapidly than BMAL1 proteins after the duplication, suggesting an as-yet-unidentified function conserved in BMAL1 but not in BMAL2. mBmal2 mRNA was constitutively expressed throughout the day under light-dark cycle in the mouse hypothalamus containing suprachiasmatic nucleus, the site of the central circadian oscillator in mammals.

ARNTL Transcription Factors↗
PubMed2002

Gene expression profiling of lymphoid malignancies.

Comprehensive gene expression profiling using DNA microarrays is providing a molecular classification of cancer into disease categories that are homogeneous with respect to pathogenesis and clinical behavior. Gene expression profiling revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two molecularly distinct diseases that are derived from distinct stages of B cell differentiation and have strikingly different clinical outcomes. By contrast, chronic lymphocytic leukemia (CLL) was found to be a single disease defined by a characteristic gene expression signature. Nonetheless, gene expression profiling distinguished two clinically divergent CLL subtypes and provided evidence that signaling through the B cell antigen receptor may play a role in the clinically aggressive subtype. Gene expression analysis also illuminated the mechanism of lymphomagenesis caused by BCL-6 translocations and provided evidence that the NF-kappa B signaling pathway is a new molecular therapeutic target in DLBCL.

DNA-Binding Proteins↗
PubMed2005

Rates of protein evolution are positively correlated with developmental timing of expression during mouse spermatogenesis.

Male reproductive genes often evolve very rapidly, and sexual selection is thought to be a primary force driving this divergence. We investigated the molecular evolution of 987 genes expressed at different times during mouse spermatogenesis to determine if the rate of evolution and the intensity of positive selection vary across stages of male gamete development. Using mouse-rat orthologs, we found that rates of protein evolution were positively correlated with the developmental timing of expression. Genes expressed early in spermatogenesis had rates of divergence similar to the genome median, while genes expressed after the onset of meiosis were found to evolve much more quickly. Rates of protein evolution were fastest for genes expressed during the dramatic morphogenesis of round spermatids into spermatozoa. Late-expressed genes were also more likely to be specific to the male germline. To test for evidence of positive selection, we analyzed the ratio of nonsynonymous to synonymous changes using a maximum likelihood framework in comparisons among mouse, rat, and human. Many genes showed evidence of positive selection, and most of these genes were expressed late in spermatogenesis and were testis specific. Overall, these data suggest that the intensity of positive selection associated with the evolution of male gametes varies considerably across development and acts primarily on phenotypes that develop late in spermatogenesis.

Animals↗
PubMed1996

TCR gene recombination and alpha beta-gamma delta lineage divergence: productive TCR-beta rearrangement is neither exclusive nor preclusive of gamma delta cell development.

Two types of T lymphocytes can be generated intrathymically, distinguishable by either TCR-gamma delta or -alpha beta surface expression. Regulation of the intrathymic divergence of these cells is unresolved, at least in part because thymically derived gamma delta cells have rarely been studied. We used quantitative Southern blotting together with PCR-based cloning/sequencing and restriction fragment length polymorphism to analyze TCR-alpha and -beta gene recombination in thymically derived gamma delta cells. We found that TCR-beta gene recombination is a frequent occurrence in thymic gamma delta cells. Furthermore, not only do complete (V-D-J) TCR-beta gene rearrangements occur in thymic gamma delta cells, but the frequency of in-frame rearrangements is greater than would be predicted based upon random occurrence. In contrast, we show that thymically derived gamma delta cells do not make detectable rearrangements of the TCR-alpha locus. These studies clearly demarcate a point for alpha beta vs gamma delta commitment in the thymus, after TCR-beta but before TCR-alpha gene recombination. Further, while our data support gamma delta lineage commitment as a consequence of successful TCR-gamma and -delta gene rearrangement, we do not find support for a competitive model of lineage commitment, since productive TCR-beta gene rearrangement does not necessarily relegate cells to the alpha beta lineage.

Animals↗
PubMed2006

In silico identification and comparative analysis of differentially expressed genes in human and mouse tissues.

BACKGROUND: Screening for differentially expressed genes on the genomic scale and comparative analysis of the expression profiles of orthologous genes between species to study gene function and regulation are becoming increasingly feasible. Expressed sequence tags (ESTs) are an excellent source of data for such studies using bioinformatic approaches because of the rich libraries and tremendous amount of data now available in the public domain. However, any large-scale EST-based bioinformatics analysis must deal with the heterogeneous, and often ambiguous, tissue and organ terms used to describe EST libraries. RESULTS: To deal with the issue of tissue source, in this work, we carefully screened and organized more than 8 million human and mouse ESTs into 157 human and 108 mouse tissue/organ categories, to which we applied an established statistic test using different thresholds of the p value to identify genes differentially expressed in different tissues. Further analysis of the tissue distribution and level of expression of human and mouse orthologous genes showed that tissue-specific orthologs tended to have more similar expression patterns than those lacking significant tissue specificity. On the other hand, a number of orthologs were found to have significant disparity in their expression profiles, hinting at novel functions, divergent regulation, or new ortholog relationships. CONCLUSION: Comprehensive statistics on the tissue-specific expression of human and mouse genes were obtained in this very large-scale, EST-based analysis. These statistical results have been organized into a database, freely accessible at our website http://gln.ibms.sinica.edu.tw/product/HMDEG/EST/index.php, for easy searching of human and mouse tissue-specific genes and for investigating gene expression profiles in the context of comparative genomics. Comparative analysis showed that, although highly tissue-specific genes tend to exhibit similar expression profiles in human and mouse, there are significant exceptions, indicating that orthologous genes, while sharing basic genomic properties, could result in distinct phenotypes.

Animals↗
PubMed2004

From wild wolf to domestic dog: gene expression changes in the brain.

Despite the relatively recent divergence time between domestic dogs (Canis familiaris) and gray wolves (Canis lupus), the two species show remarkable behavioral differences. Since dogs and wolves are nearly identical at the level of DNA sequence, we hypothesize that the two species may differ in patterns of gene expression. We compare gene expression patterns in dogs, wolves and a close relative, the coyote (Canis latrans), in three parts of the brain: hypothalamus, amygdala and frontal cortex, with microarray technology. Additionally, we identify genes with region-specific expression patterns in all three species. Among the wild canids, the hypothalamus has a highly conserved expression profile. This contrasts with a marked divergence in domestic dogs. Real-time PCR experiments confirm the altered expression of two neuropeptides, CALCB and NPY. Our results suggest that strong selection on dogs for behavior during domestication may have resulted in modifications of mRNA expression patterns in a few hypothalamic genes with multiple functions. This study indicates that rapid changes in brain gene expression may not be exclusive to the development of human brains. Instead, they may provide a common mechanism for rapid adaptive changes during speciation, particularly in cases that present strong selective pressures on behavioral characters.

Animals↗
PubMed2005

Differential expression of inducible nitric oxide synthase and cytokine mRNA in chicken lines divergent for cutaneous hypersensitivity response.

Phytohemagglutinin (PHA)-induced delayed-type hypersensitivity is an immunocompetent trait considered an indicator of cell-mediated immune or T-cell responses. Divergent selection was performed to generate high and low lines for response to PHA-P. Extreme-responder birds of the F2 generation in each line were used to study possible differences in macrophage activity and the associated functional genes. To evaluate macrophage activity, nitric oxide (NO) was estimated both systemically in serum and in in vitro monocyte culture. Semi-quantitative RT-PCR was used to detect the differential mRNA expression patterns of iNOS and MIP-1beta in monocyte culture, whereas T(H)1 cytokines (IL-2 and IFN-gamma) were studied in peripheral blood mononuclear cells (PBMC) at different time intervals after lipopolysaccharide (LPS) induction. The high line showed strong systemic, as well as in vitro NO production, compared to the low line, upon stimulation with NDV and LPS, similar to early and high iNOS mRNA expression. Following the pattern of iNOS gene expression, an early strong expression of cytokines with powerful iNOS-inducing action, such as IFN-gamma and the chemokine MIP-1beta, was observed in the high line. In contrast, for response to PHA-P, low expression of IL-2 was observed in the high compared to the low line. In conclusion, the study revealed that divergent selection for response to PHA-P resulted in a divergent effect on T(H)1 cell activity, resulting in altered macrophage function in chickens. Selection, based on response to PHA-P, could lead to more resistant birds or birds with an enhanced immune response.

Animals↗
PubMed2002

An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus: a study of 54 cases emphasizing the importance of using a panel because of overlap in immunoreactivity for individual antibodies.

The expression of desmin, h-caldesmon, calponin, CD10, CD34, CD99, inhibin, and keratin (AE1/3-Cam 5.2) was studied in 10 conventional leiomyomas, 9 highly cellular leiomyomas, 9 epithelioid smooth muscle tumors, 9 leiomyosarcomas, 10 endometrial stromal tumors (4 with smooth muscle metaplasia), and 7 uterine tumors resembling ovarian sex cord tumors (UTROSCTs). c-kit expression was tested in 10 endometrial stromal tumors, 7 UTROSCTs, and 9 leiomyosarcomas. Desmin was positive in almost all smooth muscle tumors except those of epithelioid type, which were positive in only about half of the cases. It also stained areas of smooth muscle differentiation in endometrial stromal tumors and five of seven UTROSCTs. h-caldesmon was positive in almost all nonepithelioid smooth muscle tumors and in areas of smooth muscle differentiation in endometrial stromal tumors; it was positive in only about half of the epithelioid smooth muscle tumors and negative in all UTROSCTs. Calponin was positive in most tumor types. CD10 was positive in nine of 10 endometrial stromal tumors and five of seven UTROSCTs, although very focally in the latter group. It was also expressed, however, in almost all leiomyosarcomas, almost 50% of highly cellular leiomyomas, and rarely in the other smooth muscle tumors. CD34 was negative in the tested tumors with rare exceptions. CD99 and inhibin were positive in four of seven and one of seven UTROSCTs. Keratin positivity was found in most (five of seven) UTROSCTs and occasionally in smooth muscle tumors (seven of 37). c-kit was negative in all endometrial stromal tumors, UTROSCTs, and leiomyosarcomas. The major conclusions of this study are as follows: 1) Pure endometrial stromal tumors are usually desmin negative. 2) In contrast to some previous studies, CD10 expression was often seen in smooth muscle tumors, including most leiomyosarcomas and almost half of highly cellular leiomyomas. As a result, a panel of CD10, h-caldesmon, and desmin should be used and will distinguish endometrial stromal tumors from highly cellular leiomyomas in most cases. 3) In contrast to a previous study, no significant differences in immunoreactivity were seen between h-caldesmon and desmin in tumors with smooth muscle differentiation. 4) The absence of h-caldesmon in UTROSCTs helps separate them from epithelioid smooth muscle tumors. 5) UTROSCTs may express epithelial, stromal, and smooth muscle markers, suggesting divergent differentiation. 6) Our study shows less frequent inhibin expression in the sex cord-like elements of the UTROSCTs than in other studies. 7) c-kit may help distinguish metastatic endometrial stromal tumors of the uterus (c-kit negative) from gastrointestinal stromal tumors (c-kit positive). 8) CD34, CD99, and keratin have no or minimal role in this area, but keratin positivity in smooth muscle tumors should not lead to their confusion with epithelial tumors.

Adenosine Triphosphatases↗
PubMed2001

Cloning of BUG demonstrates the existence of a brown preadipocyte distinct from a white one.

BACKGROUND: Several indirect arguments agree with the existence of a brown preadipocyte distinct from a white one. Nevertheless, to date, no molecular marker has been available to directly in vivo demonstrate this hypothesis. OBJECTIVE: The aim of this study was to find a gene expressed in brown preadipocyte but not in white and to use it as a molecular marker to analyse brown preadipocyte recruitment in different physiological and physiopathological situations. METHOD: Differential display was performed on stromal-vascular and adipocyte fractions of white and brown adipose tissues in rat. RESULTS: We identified a new gene, BUG, preferentially expressed in the stromal-vascular fraction of brown fat vs other adipose tissues fractions in adult rat. This RNA is also highly expressed in heart and, to a lesser extent, in other tissues such as kidney and brain. The BUG transcript is detected by in situ hybridization in putative preadipocytes within brown adipose tissue. Its level is transiently and specifically up-regulated during early stages of brown preadipocyte differentiation in a primary culture system, before the acquisition of late brown adipocyte phenotype. During development, BUG can be detected before the emergence of UCP-1 expression. In adult rats, BUG expression is inversely associated to brown adipose tissue (BAT) activation during cold exposure as well as in obese animals. CONCLUSIONS: The pattern of BUG expression agrees with an early divergence between brown and white adipocyte lineages. It also reveals the existence of a pool of committed brown preadipocytes within BAT that are recruited during cold exposure. BUG expression is increased in obese animals, suggesting that an early defect in brown preadipocyte differentiation could account for impaired BAT function in genetically obese rats.

Adipocytes↗
PubMed1992

Comparative analysis of the beta transducin family with identification of several new members including PWP1, a nonessential gene of Saccharomyces cerevisiae that is divergently transcribed from NMT1.

While investigating the expression of the Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase gene (NMT: E.C. 2.3.1.97) by Northern blot analysis, we observed another RNA transcript whose expression resembled that of NMT1 during meiosis and was derived from a gene located less than 1 kb immediately upstream of NMT1. This new gene, designated PWP1 (for periodic tryptophan protein), is divergently transcribed from NMT1 and encodes a 576-residue protein. Null mutants of PWP1 are viable, but their growth is severely retarded and steady-state levels of several cellular proteins (including at least two proteins that label with exogenous [3H]myristic acid) are drastically reduced. New methods for database searching and assessing the statistical significance of sequence similarities identify PWP1 as a member of the beta-transducin protein superfamily. Two other previously unrecognized beta-transducin-like proteins (S. cerevisiae MAK11 and D. discoideum AAC3) were also identified, and an unexpectedly high degree of sequence homology was found between a Chlamydomonas beta-like polypeptide and the C12.3 gene of chickens. A systematic and quantitative comparative analysis resulted in classifying all beta-transducin-like sequences into 11 nonorthologous families. Based on specific sequence attributes, however, not all beta-transducin-like sequences are expected to be functionally similar, and quantitative criteria for inferring functional analogies are discussed. Possible roles of repetitive tryptophan residues in proteins are also considered.

Acyltransferases↗
PubMed2004

Cloning and expression of p-hydroxyphenylacetate 3-hydroxylase from Acinetobacter baumannii: evidence of the divergence of enzymes in the class of two-protein component aromatic hydroxylases.

The genes encoding for the reductase and oxygenase components of p-hydroxyphenylacetate 3-hydroxylase from Acinetobacter baumannii were cloned and expressed in an E. coli system. The recombinant enzymes were purified and shown to have the same catalytic properties as the native enzyme. Sequence analysis and biochemical studies indicate that the enzyme represents a novel prototype of enzyme in the two-protein component class of aromatic hydroxylases. The C2 component shows little similarity to other oxygenases in the same class, correlating with its uniquely broad flavin specificity. Analysis of the C1 reductase sequence indicates that the binding sites of flavin and NADH mainly reside in the N-terminal half while the C-terminal half may be responsible for HPA-stimulation of NADH oxidation.

Acinetobacter baumannii↗
PubMedDate not supplied

Multilocus enzymes in man.

Two or more separate loci may be concerned in coding for enzyme proteins with the same or very similar catalytic properties. The phenomenon appears to be remarkably common and rough estimates suggest that perhaps 50% or more of structural loci coding for enzyme proteins are concerned with these so-called multilocus enzymes. The separate enzymes in such a multilocus set ressemble each other not only in their enzyme properties, but also in subunit structures and in molecular sizes. However there are often remarkable differences in expression of the several loci of a set from tissue to tissue. Such sets of loci probably arose in evolution by gene duplications with subsequent divergence by point mutations. Tissue differentiation in expression suggests that, pari passu with the divergence of the structural genes, there was an evolution of genetic regulating systems controlling their tissue expression.

Biological Evolution↗
PubMed2001

CRP modulates fis transcription by alternate formation of activating and repressing nucleoprotein complexes.

The DNA architectural proteins FIS and CRP are global regulators of transcription in Escherichia coli involved in the adjustment of cellular metabolism to varying growth conditions. We have previously demonstrated that FIS modulates the expression of the crp gene by functioning as its transcriptional repressor. Here we show that in turn, CRP is required to maintain the growth phase pattern of fis expression. We demonstrate the existence of a divergent promoter in the fis regulatory region, which reduces transcription of the fis promoter. In the absence of FIS, CRP activates fis transcription, thereby displacing the polymerase from the divergent promoter, whereas together FIS and CRP synergistically repress fis gene expression. These results provide evidence for a direct cross-talk between global regulators of cellular transcription during the growth phase. This cross-talk is manifested in alternate formation of functional nucleoprotein complexes exerting either activating or repressing effects on transcription.

Base Sequence↗