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Transcription FactorsTranscription, GeneticGATA4 Transcription FactorGATA6 Transcription FactorGATA2 Transcription FactorDNA-Binding ProteinsPromoter Regions, GeneticGATA3 Transcription FactorGATA Transcription FactorsGATA1 Transcription FactorSp1 Transcription FactorGene Expression RegulationMolecular Sequence DataBase SequenceBinding SitesTranscriptional ActivationGATA5 Transcription FactorTrans-ActivatorsBasic Helix-Loop-Helix Transcription FactorsRNA, MessengerProtein BindingNuclear ProteinsTranscription Factor AP-1Gene Expression Regulation, DevelopmentalRepressor ProteinsHomeodomain ProteinsCell LineForkhead Transcription FactorsSignal TransductionAmino Acid SequenceDNAMutationBasic-Leucine Zipper Transcription FactorsCell DifferentiationTranscription Factor AP-2Cell NucleusTransfectionGenes, ReporterChromatin ImmunoprecipitationKruppel-Like Transcription FactorsTranscription Factors, TFIIZinc FingersCells, CulturedYY1 Transcription FactorHeLa CellsSTAT3 Transcription FactorTranscription Factor TFIIDNFATC Transcription FactorsEnhancer Elements, GeneticReverse Transcriptase Polymerase Chain ReactionActivating Transcription Factor 3Electrophoretic Mobility Shift AssayTranscription Initiation SiteSp3 Transcription FactorNF-kappa BPaired Box Transcription FactorsRegulatory Sequences, Nucleic AcidGene Expression ProfilingActivating Transcription Factor 2Transcription Factor TFIIBCloning, MolecularRecombinant Fusion ProteinsE2F1 Transcription FactorRNA Polymerase IIMEF2 Transcription FactorsBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsPlasmidsGene ExpressionGene Expression Regulation, FungalLuciferasesErythroid-Specific DNA-Binding FactorsTCF Transcription FactorsProtein Structure, TertiaryMicrophthalmia-Associated Transcription FactorCell Line, TumorSTAT1 Transcription FactorChromatinActivating Transcription FactorsOligonucleotide Array Sequence AnalysisHelix-Loop-Helix MotifsPhosphorylationTranscription Factor RelAE2F Transcription FactorsSaccharomyces cerevisiaeModels, BiologicalMice, KnockoutSequence Homology, Amino AcidSaccharomyces cerevisiae ProteinsMice, TransgenicProto-Oncogene ProteinsGene Expression Regulation, PlantActivating Transcription Factor 4Transcription Factor 7-Like 1 ProteinActivating Transcription Factor 1Cyclic AMP Response Element-Binding ProteinBlotting, WesternDown-RegulationTATA BoxTranscription Factor TFIIIAModels, Genetic

Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery. (1/233)

The GATA-6 transcription factor is expressed in quiescent vascular smooth muscle cells (VSMCs) in culture, and levels of its transcript are rapidly downregulated on mitogen stimulation. In this study, we demonstrate that the GATA-6 transcript, protein, and DNA-binding activity are downregulated in rat carotid arteries on balloon injury. Downregulation was detected at 1 and 3 days after injury and recovered by 7 days. To assess the role of GATA-6 downregulation in injury-induced vascular lesion formation, adenoviral vectors were used to express wild-type human GATA-6 cDNA (Ad-GATA6) or an inactive mutant cDNA that lacks a portion of the zinc-finger domain (Ad-GATA6DeltaZF). Adenovirus-mediated GATA-6 gene transfer to the vessel wall after balloon injury partially restored the levels of GATA-6 protein and DNA-binding activity to before injury levels. The local delivery of Ad-GATA6 but not Ad-GATA6DeltaZF inhibited lesion formation by 46% relative to saline control and 50% relative to a control adenovirus that expressed lacZ. Local delivery of Ad-GATA6 also reversed changes in the expression patterns of smooth muscle myosin heavy chain, smooth muscle alpha-actin, calponin, vinculin, metavinculin, and proliferating cell nuclear antigen that are associated with injury-induced VSMC phenotypic modulation. These data indicate that the injury-induced downregulation of GATA-6 is an essential feature of VSMC phenotypic modulation that contributes to vessel lesion formation.  (+info)

Cooperative interaction between GATA-4 and GATA-6 regulates myocardial gene expression. (2/233)

Two members of the GATA family of transcription factors, GATA-4 and GATA-6, are expressed in the developing and postnatal myocardium and are equally potent transactivators of several cardiac promoters. However, several in vitro and in vivo lines of evidence suggest distinct roles for the two factors in the heart. Since identification of the endogenous downstream targets of GATA factors would greatly help to elucidate their exact functions, we have developed an adenovirus-mediated antisense strategy to specifically inhibit GATA-4 and GATA-6 protein production in postnatal cardiomyocytes. Expression of several endogenous cardiac genes was significantly down-regulated in cells lacking GATA-4 or GATA-6, indicating that these factors are required for the maintenance of the cardiac genetic program. Interestingly, transcription of some genes like the alpha- and beta-myosin heavy-chain (alpha- and beta-MHC) genes was preferentially regulated by GATA-4 due, in part, to higher affinity of GATA-4 for their promoter GATA element. However, transcription of several other genes, including the atrial natriuretic factor and B-type natriuretic peptide (ANF and BNP) genes, was similarly down-regulated in cardiomyocytes lacking one or both GATA factors, suggesting that GATA-4 and GATA-6 could act through the same transcriptional pathway. Consistent with this, GATA-4 and GATA-6 were found to colocalize in postnatal cardiomyocytes and to interact functionally and physically to provide cooperative activation of the ANF and BNP promoters. The results identify for the first time bona fide in vivo targets for GATA-4 and GATA-6 in the myocardium. The data also show that GATA factors act in concert to regulate distinct subsets of genes, suggesting that combinatorial interactions among GATA factors may differentially control various cellular processes.  (+info)

The transcription factor GATA6 is essential for early extraembryonic development. (3/233)

The gene coding for the murine transcription factor GATA6 was inactivated by insertion of a beta-galactosidase marker gene. The analysis of heterozygote GATA6/lacZ mice shows two inductions of GATA6 expression early in development. It is first expressed at the blastocyst stage in part of the inner mass and in the trophectoderm. The second wave of expression is in parietal endoderm (Reichert's membrane) and the mesoderm and endoderm that form the heart and gut. Inactivation leads to a lethality shortly after implantation (5.5 days postcoitum). Chimeric experiments show this to be caused by an indirect effect on the epiblast due to a defect in an extraembryonic tissue.  (+info)

Reciprocal changes in the expression of transcription factors GATA-4 and GATA-6 accompany adrenocortical tumorigenesis in mice and humans. (4/233)

While certain genetic changes are frequently found in adrenocortical carcinoma cells, the molecular basis of adrenocortical tumorigenesis remains poorly understood. Given that the transcription factors GATA-4 and GATA-6 have been implicated in gene expression and cellular differentiation in a variety of tissues, including endocrine organs such as testis, we have now examined their expression in the developing adrenal gland, as well as in adrenocortical cell lines and tumors from mice and humans. Northern blot analysis and in situ hybridization revealed abundant GATA-6 mRNA in the fetal and postnatal adrenal cortex of the mouse. In contrast, little or no GATA-4 expression was detected in adrenal tissue during normal development. In vivo stimulation with ACTH or suppression with dexamethasone did not affect the expression of GATA-4 or GATA-6 in the murine adrenal gland. To assess whether changes in the expression of GATA-4 or GATA-6 accompany adrenocortical tumorigenesis, we employed an established mouse model. When gonadectomized, inhibin alpha/SV40 T-antigen transgenic mice develop adrenocortical tumors in a gonadotropin-dependent fashion. In striking contrast to the normal adrenal glands, GATA-6 mRNA was absent from adrenocortical tumors or tumor-derived cell lines, while GATA-4 mRNA and protein were abundantly expressed in the tumors and tumor cell lines. Analogous results were obtained with human tissue samples; GATA-4 expression was detected in human adrenocortical carcinomas but not in normal tissue, adenomas, or pheochromocytomas. Taken together these results suggest different roles for GATA-4 and GATA-6 in the adrenal gland, and implicate GATA-4 in adrenal tumorigenesis. Immunohistochemical detection of GATA-4 may serve as a useful marker in the differential diagnosis of human adrenal tumors.  (+info)

Synergistic effects of nuclear factors--GATA, VBP and ER in potentiating vitellogenin gene transcription. (5/233)

The Oreochromis aureus vitellogenin (OaVtg) gene contains three imperfect oestrogen response elements (EREs) and GATA and VBP (vitellogenin binding protein) binding sites. An analysis of the promoter indicates that the 5'-flanking region up to position -625 is sufficient to mediate E(2) control. Furthermore, transfection of deletion and mutagenised promoters indicates that both GATA and VBP synergise with ER, and thus contribute to the regulation of the endogenous OaVtg gene. These findings support the notion that the interplay of promoter elements mediates proper hormone-dependent and tissue-specific expression of the OaVtg gene, regardless of non-consensus sequence context of EREs and VBP.  (+info)

A role for GATA-4/5/6 in the regulation of Nkx2.5 expression with implications for patterning of the precardiac field. (6/233)

Interactions between the key regulatory genes of the cardiogenic pathway, including those from the GATA and Nkx2 transcription factor families, are not well defined. Treating neurula-stage Xenopus embryos with retinoic acid (RA) causes a specific block in cardiomyocyte development that correlates with a progressive reduction in the region of the presumptive heart-forming region expressing Nkx2.5. In contrast, RA does not block expression of the GATA-4/5/6 genes, which are transcribed normally in an overlapping pattern with Nkx2.5 throughout cardiogenesis. Instead, GATA-4/5/6 transcription levels are increased, including an expansion of the expression domain corresponding to lateral plate mesoderm that is part of the early heart field, but that normally is progressively restricted in its ability to contribute to the myocardium. GATA-dependent regulatory sequences of the Nkx2.5 gene that implicate GATA-4/5/6 as upstream positive regulators were described recently. However, our experiments also indicate that GATA factors might normally antagonize transcription of Nkx2.5. To test this hypothesis we generated a dominant negative isoform of GATA-4 (SRG4) capable of inhibiting transcription of GATA-dependent target genes. Ectopic expression of SRG4 results in a transient expansion of the Nkx2.5 transcript pattern, indicating that a normal function of GATA factors is to limit the boundary of the Nkx2.5 expression domain to the most anterior ventral region of the heart field. Regulatory mechanisms altered by excess RA must function normally to limit GATA-4/5/6 expression levels, to define the region of Nkx2.5 expression and regulate myocardial differentiation.  (+info)

The human and mouse GATA-6 genes utilize two promoters and two initiation codons. (7/233)

GATA-6 has been implicated in the regulation of myocardial differentiation during cardiogenesis. To determine how its expression is controlled, we have characterized the human and mouse genes. We have mapped their transcriptional start sites and demonstrate that two alternative promoters and 5' noncoding exons are utilized. Both transcript isoforms are expressed in the same tissue-specific and developmental stage-specific pattern, and their ratio appears similar wherever examined. The more upstream noncoding exon showed a substantial degree of homology between the two mammalian species, suggesting a conserved regulatory function. Moreover, in transfection assays we show that elements within this exon act to promote its transcription. Positive regulatory elements that effect transcription from the more downstream exon were not apparent in this assay, revealing a regulatory distinction between the two promoters. We also demonstrate alternative initiator codon usage in both the human and mouse GATA-6 genes. Both isoforms of the protein are synthesized in vitro regardless of which 5' noncoding exon is present in the RNA, although the larger protein has greater transcriptional activation potential in transfection assays. Thus, GATA-6 function in the cell is controlled by a complex interplay of transcriptional and translational regulation.  (+info)

Direct activation of a GATA6 cardiac enhancer by Nkx2.5: evidence for a reinforcing regulatory network of Nkx2.5 and GATA transcription factors in the developing heart. (8/233)

The zinc finger transcription factors GATA4, -5, and -6 and the homeodomain protein Nkx2.5 are expressed in the developing heart and have been shown to activate a variety of cardiac-specific genes. To begin to define the regulatory relationships between these cardiac transcription factors and to understand the mechanisms that control their expression during cardiogenesis, we analyzed the mouse GATA6 gene for regulatory elements sufficient to direct cardiac expression during embryogenesis. Using beta-galactosidase fusion constructs in transgenic mice, a 4.3-kb 5' regulatory region that directed transcription specifically in the cardiac lineage, beginning at the cardiac crescent stage, was identified. Thereafter, transgene expression became compartmentalized to the outflow tract, a portion of the right ventricle, and a limited region of the common atrial chamber of the embryonic heart. Further dissection of this regulatory region identified a 1.8-kb cardiac-specific enhancer that recapitulated the expression pattern of the larger region when fused to a heterologous promoter and a smaller 500-bp subregion that retained cardiac expression, but was quantitatively weaker. The GATA6 cardiac enhancer contained a binding site for Nkx2.5 that was essential for cardiac-specific expression in transgenic mice. These studies demonstrate that GATA6 is a direct target gene for Nkx2.5 in the developing heart and reveal a mutually reinforcing regulatory network of Nkx2.5 and GATA transcription factors during cardiogenesis.  (+info)