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Results for “tissue specificity”

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PubMed1997

Patterning the expression of a tissue-specific transcription factor in embryogenesis: HNF1 alpha gene activation during Xenopus development.

Tissue-specific transcription factors play an essential role in establishing cell identity during development. We review our knowledge of the molecular events involved in the activation of the gene encoding the tissue-specific transcription factor HNF1 alpha (LFB1). The available data suggest that the maternal factors OZ-1, HNF4 alpha and HNF4 beta act as initial activators of the HNF1 alpha promoter. We present evidence suggesting that the mesoderm-inducing factor activin A plays a critical role by acting through the HNF4 binding site of the HNF1 alpha promoter. The activity of this embryonic morphogen seems to form a gradient opposing the distribution of the maternal HNF4 proteins that are concentrated at the animal pole of the egg. After zygotic gene transcription the HNF1 alpha-related transcription factor HNF1 beta accumulates faster than HNF1 alpha itself and thus is likely to contribute to the activation of the HNF1 alpha transcription via the HNF1 binding site. The cofactor of the HNF1 proteins (DCoH) is present throughout development and thus cannot limit the activation potential of HNF1 alpha in early development. Our results provide a detailed description of setting up the expression pattern of a tissue-specific transcription factor during embryogenesis.

Activins↗

PubMed1997

Synergistic role of E1A-binding proteins and tissue-specific transcription factors in differentiation.

In this review, the complex relationship between tissue-specific transcription factors and genes regulating cell cycle is taken into account. Both E1-A binding proteins belonging to the family of the retinoblastoma gene product and the CBP/p300 coactivator of transcription interact physically and functionally with tissue-specific transcription factor. The relationship between these two classes of molecules regulates cell fate in differentiating cells, deciding whether cells continue to replicate, undergo apoptosis or terminally differentiate. We provide here an update on the recent advances in this field and some models of interaction between E1A binding protein and tissue-specific transcription factors.

Adenovirus E1A Proteins↗

PubMed1991

Tissue-specific expansion of uridine pools in mice. Effects of benzylacyclouridine, dipyridamole and exogenous uridine.

The concentration of uridine (Urd) in murine tissues appears to be controlled by Urd catabolism, concentrative Urd transport, and the non-concentrative, facilitated diffusion of Urd. Previous reports document the tissue-specific disruption of these processes, and subsequently intracellular pools of free Urd in mice, by the administration of exogenous Urd (250 mg/kg) or the Urd phosphorylase (EC 2.4.2.3; uracil:ribose-1-phosphate phosphotransferase) inhibitor 5-benzylacyclouridine (BAU) (240 mg/kg). We now report the effect of combinations of BAU (120 mg/kg, p.o.), the nucleoside transport inhibitor dipyridamole (DP) (25 mg/kg, i.p.), and exogenous Urd (250 mg/kg, i.v.) on Urd pools in mice. This dose of BAU increased Urd pools 2- to 6-fold, in a tissue-specific manner, for up to 5 hr. DP increased Urd pools 3-fold in spleen, over a 4-hr period, but did not affect other tissues. Administration of BAU 1 hr prior to exogenous Urd resulted in a 50- to 100-fold expansion of tissue normal after 6 hr. Administration of DP 1 hr prior to exogenous Urd caused a tissue-specific 40- to 100-fold increase in Urd pools which, except in spleen, returned to normal within 2 hr. The marked additive effects of these combinations were in contrast to those obtained following the administration of BAU 1 hr prior to DP. This regimen increased Urd pools from 4- to 9-fold, in a tissue-specific manner. In addition, Urd pools remained elevated for up to 9 hr, except in spleen where the Urd concentration was elevated for up to 15 hr. Analysis of enzyme activities indicated that DP does not enhance the inhibitory effect of BAU against murine liver Urd phosphorylase. However, DP did inhibit plasma clearance of BAU, and this effect may partially explain the apparent synergistic effect of this combination. In spite of the prolonged and dramatic expansion of tissue Urd pools produced by BAU + DP, the total Ura nucleotide content in spleen, gut and colon tumor 38 (CT38) increased by less than 70% over a 12-hr period following administration of this combination. These findings are discussed in light of their biochemical and therapeutic implications.

Administration, Oral↗

PubMed2006

DNA motifs in human and mouse proximal promoters predict tissue-specific expression.

Comprehensive identification of cis-regulatory elements is necessary for accurately reconstructing gene regulatory networks. We studied proximal promoters of human and mouse genes with differential expression across 56 terminally differentiated tissues. Using in silico techniques to discover, evaluate, and model interactions among sequence elements, we systematically identified regulatory modules that distinguish elevated from inhibited expression in the corresponding transcripts. We used these putative regulatory modules to construct a single predictive model for each of the 56 tissues. These predictors distinguish tissue-specific elevated from inhibited expression with statistical significance in 80% of the tissues (45 of 56). The predictors also reveal synergy between cis-regulatory modules and explain large-scale tissue-specific differential expression. For testis and liver, the predictors include computationally predicted motifs. For most other tissues, the predictors reveal synergy between experimentally verified motifs and indicate genes that are regulated by similar tissue-specific machinery. The identification in proximal promoters of cis-regulatory modules with tissue-specific activity lays the groundwork for complete characterization and deciphering of cis-regulatory DNA code in mammalian genomes.

Animals↗

PubMed1990

Tissue specificity of tropomyosin from the crayfish, Cambarus clarki.

The molecular heterogeneity and tissue specificity of crustacean tropomyosin were investigated, using muscle and nonmuscle tissues from the crayfish, Cambarus clarki. In muscle, three types of tropomyosin isoforms were found on two-dimensional gel electrophoresis. One of them was specific to cardiac muscle, and the other two were shared by skeletal and visceral muscles. In nonmuscle tissues, four types of isoforms were found on two-dimensional gel electrophoresis and in immunoreplica tests using an antiserum against crayfish skeletal muscle tropomyosin. Two of them were common to the muscle isoforms, but the other two were not detected in muscles. Furthermore, nonmuscle tissues contained several peculiar isoforms, the electrophoretic mobilities of which were considerably higher than those of the other isoforms mentioned above. When tropomyosin was purified from the mid-gut gland, these isoforms with high mobilities were found in the crude tropomyosin preparation. These results showed that the crayfish tropomyosin was heterogeneous and that the isoforms were distributed in a tissue-specific manner, like vertebrate tropomyosin. However, the results did not coincide with those of our previous study on horseshoe crab tropomyosin, which showed molecular heterogeneity but no tissue specificity. In view of the difference in the isoform distributions between the two major groups (Crustacea and Merostomata) of Arthropoda, the significance of the tissue specificity of tropomyosin isoforms was discussed.

Animals↗

PubMed1992

Sex-dependent expression and clofibrate inducibility of cytochrome P450 4A fatty acid omega-hydroxylases. Male specificity of liver and kidney CYP4A2 mRNA and tissue-specific regulation by growth hormone and testosterone.

The induction of liver cytochrome P450 4A-catalyzed fatty acid omega-hydroxylase activity by clofibrate and other peroxisome proliferators has been proposed to be causally linked to the ensuing proliferation of peroxisomes in rat liver. Since female rats are less responsive than males to peroxisome proliferation induced by clofibrate, the influence of gender and hormonal status on the basal and clofibrate-inducible expression of the 4A P450s was examined. Northern blot analysis using gene-specific oligonucleotide probes revealed that in the liver, P450 4A1 and 4A3 mRNAs are induced to a much greater extent in male as compared to female rats following clofibrate treatment, whereas P450 4A2 mRNA is altogether absent from female rat liver. Male-specific expression of P450 4A2 mRNA was also observed in kidney. Western blot analysis indicated that a similar sex dependence characterizes both the basal expression and the clofibrate inducibility of the corresponding P450 4A proteins. This suggests that the lower responsiveness of female rats to clofibrate-induced peroxisome proliferation may reflect the lower inducibility of the P450 4A fatty acid hydroxylase enzymes in this sex. Investigation of the contribution of pituitary-dependent hormones to the male-specific expression of 4A2 revealed that this P450 mRNA is fully suppressed in liver following exposure to the continuous plasma growth hormone profile that characterizes adult female rats; in this and other regards liver P450 4A2 is regulated in a manner that is similar, but not identical to, P450 3A2, a male-specific testosterone 6 beta-hydroxylase. In contrast, kidney 4A2 expression, although also male-specific, was not suppressed by continuous growth hormone treatment, but was regulated by pathways that, in part, involve testosterone as a positive regulator. The male-specific expression of liver and kidney P450 4A2 is thus under the control of distinct pituitary-dependent hormones acting in a tissue-specific manner.

Animals↗

PubMed2002

Identification and characterization of a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors.

Gene activation mediated by nuclear receptors is regulated in a tissue-specific manner and requires interactions between nuclear receptors and their cofactors. Here, we identified and characterized a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. GT198 was originally described as a genomic transcript that mapped to the human breast cancer susceptibility locus 17q12-q21 with unknown function. We show that GT198 exhibits a tissue-specific expression pattern in which its mRNA is elevated in testis, spleen, thymus, pituitary cells, and several cancer cell lines. GT198 is a 217-amino-acid nuclear protein that contains a leucine zipper required for its dimerization. In vitro binding and yeast two-hybrid assays indicated that GT198 interacted with nuclear receptors through their DNA-binding domains. GT198 potently stimulated transcription mediated by estrogen receptor alpha and beta, thyroid hormone receptor beta1, androgen receptor, glucocorticoid receptor, and progesterone receptor. However, the action of GT198 was distinguishable from that of the ligand-binding domain-interacting nuclear receptor coactivators, such as TRBP, CBP, and SRC-1, with respect to basal activation and hormone sensitivity. Furthermore, protein kinase A, protein kinase C, and mitogen-activated protein kinase can phosphorylate GT198 in vitro, and cotransfection of these kinases regulated the transcriptional activity of GT198. These data suggest that GT198 is a tissue-specific, kinase-regulated nuclear receptor coactivator that interacts with the DNA-binding domains of nuclear receptors.

Amino Acid Sequence↗

PubMedDate not supplied

Tissue-specific expression in mouse P815 mastocytoma cells of the cloned rat alpha-subunit gene of the high-affinity receptor for immunoglobulin E.

The high-affinity multisubunit receptor for IgE, Fc epsilon RI, is expressed in vivo in a tissue-specific manner, being found only on mast cells, basophils and epidermal Langerhans cells. The expression of the rat Fc epsilon RI alpha-subunit transcript has been examined here in the mouse mastocytoma cell line, P815, which does not express the endogenous mouse Fc epsilon RI alpha- or beta-subunit transcripts. These studies indicate that an exogenously introduced rat alpha-subunit gene can be faithfully expressed in P815 cells, while no transcripts are produced in the mouse or rat B-lymphoid cell lines, SP2/0 and IR162, respectively. Therefore, in contrast to both B-cell lines, factors necessary for the tissue-specific expression of the alpha-subunit mRNA are present in the P815 cell line, yielding a correctly processed mRNA transcript; nevertheless, this tissue-specific expression is not rigorously species specific. Although the mechanism responsible for these observations is unknown, these results do imply that a specific cis-trans element interaction occurs between this transcriptional unit and factors in the P815 cells that control fidelity of tissue-specific mRNA synthesis and processing from the Fc epsilon RI alpha-subunit gene. Consequently, this reconstructed rat Fc epsilon RI alpha-subunit gene contains minimally sufficient cis elements for tissue-specific expression of mRNA, and so, the P815 cell line should be useful to define these requisite DNA cis elements of the gene, as well as the trans factors from P815 necessary for this process.

Animals↗

PubMed1987

Family of Na+,K+-ATPase genes. Intra-individual tissue-specific restriction fragment length polymorphism.

Intra-individual tissue-specific restriction fragment length polymorphism (RFLP) has been demonstrated in DNA isolated from different mammalian tissues using cDNAs of alpha- and beta-subunits of Na+,K+-ATPase as hybridization probes. We propose that the RFLPs could result from gene rearrangements in the gene loci for the alpha- and beta-subunits of Na+,K+-ATPase. The changes in restriction patterns have been shown to occur during embryonic development and tumor formation. In addition, the tissue specificity of the expression of different genes of the family of Na+,K+-ATPase genes and their low expression in tumor cells have been demonstrated.

Animals↗

PubMed2005

Accuracy of radiography in grading and tissue-specific diagnosis--a study of 200 consecutive bone tumors of the hand.

OBJECTIVE: To determine the usefulness of radiography and magnetic resonance imaging in differentiating benign from malignant bony tumors of the hand and in making a tissue-specific diagnosis. DESIGN: Two hundred consecutive bony tumors of the hand, the details of which originated from a national databank, were studied in a prospective way by radiography (100%) and by MRI (25%). All tumors were graded on a five-point scale, from certainly benign to certainly malignant, using location and morphology as diagnostic parameters. For all tumors a tissue-specific diagnosis was made, by the proposal of three possibilities in decreasing order of probability. Histological diagnosis was made by peer review, according to the WHO classification. RESULTS: By the combining of "certainly" and "probably" benign (grades I and II) and "certainly" and "probably" malignant (grades IV and V), a correct grading was obtained in 165 (82.5%) of the cases (154 of the 173 benign and 11 of the 27 malignant tumors). A correct tissue-specific diagnosis was included in the three proposed differentials in 87.5%. MRI confirmed a correct diagnosis made on radiography in 72% and improved the grading capability by correctly upgrading malignant tumors and downgrading benign tumors in, respectively, 8% and 12%. The capability to obtain a tissue-specific diagnosis improved with change of an incorrect diagnosis on radiography to a correct one on MRI in 12 cases (24%). CONCLUSION: Subjective (semiquantitative) grading on radiography by an expert group proved to be excellent when compared with the results of a quantitative analysis of individual grading parameters. Multiple logistic regression analysis of these parameters resulted in a grading formula containing only six variables. The additional value of MRI in grading was amply demonstrated. Already high accuracy of radiography, in making a tissue-specific diagnosis, improved substantially after the performance of MRI.

Adult↗

PubMed1996

Tissue-specific expression of the nonneuronal promoter of the aromatic L-amino acid decarboxylase gene is regulated by hepatocyte nuclear factor 1.

The rat aromatic l-amino acid decarboxylase (AADC) gene contains alternative promoters which direct expression of neuronal and nonneuronal mRNAs that differ only in their 5'-untranslated regions (UTRs). We have analyzed the expression of the nonneuronal promoter of the rat AADC gene in the kidney epithelial cell line LLC-PK1 and in cells which do not express the nonneuronal form of AADC by transient transfection. These studies revealed that the first 1.1 kilobases of the nonneuronal promoter, including the nonneuronal-specific 5'-UTR (Exon 1), contains sufficient information to direct tissue-specific expression. Serial deletions of this promoter localized the cis-active element to a region between -52 and -28 base pairs upstream of the nonneuronal transcription start site. An A/T-rich sequence, within this region which we have termed KL-1, was found to bind a kidney and liver-specific factor by DNase footprint analysis and was capable of directing tissue-specific expression from a heterologous promoter. Moreover, when the KL-1 sequence was mutated in the context of the entire promoter sequence, all transcriptional activity was abolished. DNA sequence comparison revealed that the KL-1 fragment is highly homologous to the binding site for hepatocyte nuclear factor-1 (HNF-1). Mobility shift studies utilizing an antibody to HNF-1 demonstrated binding of HNF-1 to the KL-1 fragment and cotransfection of HNF-1 cDNA into cells which do not express the nonneuronal form of AADC resulted in activation of transfected AADC nonneuronal promoter constructs. These results strongly suggest that the transcription factor which regulates the tissue-specific expression of the nonneuronal form of AADC mRNA is HNF-1.

Animals↗

PubMed1995

A single cis-acting element in a short promoter segment of the gene encoding the interphotoreceptor retinoid-binding protein confers tissue-specific expression.

Interphotoreceptor retinoid-binding protein (IRBP) is the major protein component of the interphotoreceptor matrix. IRBP has a highly restricted tissue-specific expression in retinal photoreceptor cells and in a subgroup of pinealocytes. With the purpose of understanding how transcriptional regulation contributes to the expression of human IRBP, we have studied a short promoter fragment (from -123 to +18, relative to the transcription start site). We demonstrate, by analysis of the expression of the lacZ reporter gene fused to this short promoter fragment in transgenic mice, that it is sufficient to confer tissue-specific expression in retinal photoreceptors and in pinealocytes. DNA/protein binding assays, performed to identify binding sites for tissue-specific trans-acting factors, have shown that an element between -45 and -58 binds a factor present only in nuclear extracts of retinoblastoma-derived cell lines, which express IRBP. An element further upstream, between -86 and -106, binds apparently ubiquitous factors. Site-directed mutagenesis was performed to disrupt a GATTAA motif included in the -45 to -58 binding site and a second inverted GATTAA motif present shortly upstream. In transgenic mice bearing the mutated version of the promoter fragment, the expression of the reporter gene was completely abolished, thus suggesting that this element is essential for tissue-specific expression. A GATTAA motif appears in the 5'-flanking regions of several photoreceptor-specific genes, suggesting that this could be the recognition site for a photoreceptor-specific factor.

Animals↗

PubMed1995

The promoter of the gene Itr1 from barley confers a different tissue specificity in transgenic tobacco.

Tissue-specific expression of the gene coding for trypsin inhibitor BTI-CMe in barley (Itr1) occurs during the first half of endosperm development. In transgenic tobacco, the Itr1 promoter drives expression of the beta-glucuronidase reporter gene not only in developing endosperm but also in embryo, cotyledons and the meristematic intercotyledonary zone of germinating seedlings. A promoter fragment extending 343 bp upstream of the translation initiation ATG codon was sufficient for full transgene expression, whereas, the proximal 83 bp segment of the promoter was inactive. Possible reasons for the differences in expression patterns are discussed.

Base Sequence↗

PubMed2006

A CTCF-dependent silencer located in the differentially methylated area may regulate expression of a housekeeping gene overlapping a tissue-specific gene domain.

The tissue-specific chicken alpha-globin gene domain represents one of the paradigms, in terms of its constitutively open chromatin conformation and the location of several regulatory elements within the neighboring housekeeping gene. Here, we show that an 0.2-kb DNA fragment located approximately 4 kb upstream to the chicken alpha-globin gene cluster contains a binding site for the multifunctional protein factor CTCF and possesses silencer activity which depends on CTCF binding, as demonstrated by site-directed mutagenesis of the CTCF recognition sequence. CTCF was found to be associated with this recognition site in erythroid cells but not in lymphoid cells where the site is methylated. A functional promoter directing the transcription of the apparently housekeeping ggPRX gene was found 120 bp from the CTCF-dependent silencer. The data are discussed in terms of the hypothesis that the CTCF-dependent silencer stabilizes the level of ggPRX gene transcription in erythroid cells where the promoter of this gene may be influenced by positive cis-regulatory signals activating alpha-globin gene transcription.

Animals↗

PubMed1997

Promoter-dependent tissue-specific expressive nature of imprinting gene, insulin-like growth factor II, in human tissues.

The insulin-like growth factor II (IGF2) is a polypeptide with structure homology to insulin which possesses mitogen activity, and imprinted with paternal allele. In order to elucidate the distribution of imprinting pattern and relationship between allele- and tissue-specific expression of IGF2 in growth and maturation of human tissues, we investigated allele-specific expression of IGF2 in a wide spectrum of normal maturated human tissues by a PCR-based assay and found monoallelic expression in all eight-type tissues tested except human adult liver. Moreover, when a RT-PCR based sensitive allele-specific primer extension for an Apa I polymorphism within exon 9 of IGF2 was used, the analysis revealed the gene was normally imprinted in placenta; in contrast to the finding with placenta, IGF2 transcripts were biallelically expressed in human adult liver. Our results have clearly demonstrated preferential paternal expression and tissue-specific imprinting pattern of IGF2 in all human tissues tested in this study. Collectively, since IGF2 expression in developing fetal and adult liver is specified by distinct promoters, these extensive observations definitively indicate that transcriptional imprinting of IGF2 is more likely a promoter dependent manner.

Adult↗

PubMedDate not supplied

Reactivity of tissue-specific antigens in N-methyl-N'-nitro-N-nitrosoguanidine-induced neoplasms and normal tissues from medaka (Oryzias latipes).

To further characterize the distribution of tissue-specific antigens in fish neoplasms, juvenile medaka were exposed to 30 mg/L of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 1 hr and allowed to grow out for up to 16 mo. Using a streptavidin peroxidase technique, keratin, vimentin, and neurofilament intermediate filament proteins, and actin and S-100 proteins were labeled in MNNG-induced neoplasms and normal medaka tissues using specific monoclonal or polyclonal antibodies. In vascular tumors, rhabdomyosarcoma, and teratoma, muscle tissues were positive for actin. Other sarcomas including hemangiopericytoma, fascial sarcoma, and undifferentiated sarcoma were negative for all antibodies tested. An unusual scale-associated neoplasm, composed of clusters of scale-forming cells surrounding spicules of scale, had keratin-positive stroma. The epithelial neoplasms were also positive for keratin, except for pancreatic acinar carcinoma, which had limited positivity. Both teratoma and olfactory carcinoma had S-100-positive intraepithelial cells morphologically reminiscent of neurosensory epithelial cells, which were S-100 positive in normal tissues. Although positive reactivity in fish tissues correlated with mammalian data, the antibodies used were raised against mammalian antigens. Therefore, a negative reaction may be indicative of lack of antibody sensitivity to specific fish antigens rather than absence of the antigen in the tissues. However, these data show that tissue-specific antigen detection may assist in elucidating the biology of neoplasia in fish.

Actins↗

PubMed2000

A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM.

Transcription factors of the CREB family control the expression of a large number of genes in response to various signaling pathways. Regulation mediated by members of the CREB family has been linked to various physiological functions. Classically, activation by CREB is known to occur upon phosphorylation at an essential regulatory site (Ser133 in CREB) and the subsequent interaction with the ubiquitous coactivator CREB-binding protein (CBP). However, the mechanism by which selectivity is achieved in the identification of target genes, as well as the routes adopted to ensure tissue-specific activation, remains unrecognized. We have recently described the first tissue-specific coactivator of CREB family transcription factors, ACT (activator of CREM in testis). ACT is a LIM-only protein which associates with CREM in male germ cells and provides an activation function which is independent of phosphorylation and CBP. Here we characterize a family of LIM-only proteins which share common structural organization with ACT. These are referred to as four-and-a-half-LIM-domain (FHL) proteins and display tissue-specific and developmentally regulated expression. FHL proteins display different degrees of intrinsic activation potential. They provide powerful activation function to both CREB and CREM when coexpressed either in yeast or in mammalian cells, specific combinations eliciting selective activation. Deletion analysis of the ACT protein shows that the activation function depends on specific arrangements of the LIM domains, which are essential for both transactivation and interaction properties. This study uncovers the existence of a family of tissue-specific coactivators that operate through novel, CBP-independent routes to elicit transcriptional activation by CREB and CREM. The future identification of additional partners of FHL proteins is likely to reveal unappreciated aspects of tissue-specific transcriptional regulation.

Amino Acid Motifs↗

PubMed1987

Tissue-specific regulation of glucocorticoid receptor mRNA by dexamethasone.

The effect of glucocorticoids on tissue-specific regulation of glucocorticoid receptor mRNA was studied in intact and adrenalectomized rats. Glucocorticoid receptor mRNA was examined by Northern blot hybridization and quantitated by slot blot hybridization using a glucocorticoid cRNA probe. Glucocorticoid receptor mRNA was greatest in the lung with the relative levels in other tissues as follows: spleen, 70%; brain, 55%; liver, 50%; kidney, 43%; heart, 35%; adrenal, 13%; and testis only 8%. A tissue-specific difference in glucocorticoid receptor mRNA accumulation was found after adrenalectomy. There was little change in glucocorticoid receptor mRNA levels in liver and lung, but the brain and kidney demonstrated a 40 and 80% increase in mRNA, respectively. In contrast, dexamethasone treatment resulted in a consistent decrease of 40-60% in the accumulation of glucocorticoid receptor mRNA in all tissues studied. These results provide in vivo evidence for the autoregulation of the glucocorticoid receptor by its homologous ligand and demonstrate the existence of tissue-specific regulation of the glucocorticoid receptor mRNA levels in states of glucocorticoid excess and depletion.

Adrenalectomy↗