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

The yeast transcriptional activator Zap1 contains two uncommon structural motifs designated zinc finger pair domains. The hallmark of this domain is the packing of two zinc finger motifs in one globular unit. One finger pair domain in Zap1 contains the AD2 transactivation domain. Zn(II) binding to this domain (ZF1/2) is kinetically labile yielding a zinc-regulated transactivator. The second finger pair domain (ZF3/4) lies within the DNA-binding domain, and it stably binds Zn(II). The goal of this study was to map the determinant conferring lability in Zn(II) binding by using finger pair chimeras. Whereas ZF2 contains the transactivation function, zinc regulation is dependent on the presence of ZF1. ZF3 can functionally replace ZF1, and a ZF3/2 finger pair retains limited zinc regulation. Replacement of ZF3 by ZF1 creating a ZF1/4 chimera was found to stably bind Zn(II), suggesting that the presence of a stable motif (ZF4) can impart binding stability on a labile motif (ZF1). Zn(II) binding in finger pair domains is dependent on the presence of both motifs. Mutations in one finger motif markedly attenuate Zn(II) binding to the second motif. Kinetic lability in Zn(II) binding was mapped to the alpha-helix of ZF2. A ZF1/ZFbeta2alpha4 chimera resembles ZF3/4 in Zn(II) binding stability in incubation studies with the Zn(II) chelators. The present results demonstrate that zinc regulation of AD activity of ZF2 is dependent on determinants in ZF1 as well as the alpha-helix segment of ZF2.
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PMID:Zinc metalloregulation of the zinc finger pair domain. 1682 33

The trace element zinc is required for proper functioning of a large number of proteins, including various enzymes. However, most zinc-containing proteins are transcription factors capable of binding DNA and are named zinc finger proteins. They form one of the largest families of transcriptional regulators and are categorized into various classes according to zinc-binding motifs. This review focuses on one class of zinc finger proteins called zinc cluster (or binuclear) proteins. Members of this family are exclusively fungal and possess the well-conserved motif CysX(2)CysX(6)CysX(5-12)CysX(2)CysX(6-8)Cys. The cysteine residues bind to two zinc atoms, which coordinate folding of the domain involved in DNA recognition. The first- and best-studied zinc cluster protein is Gal4p, a transcriptional activator of genes involved in the catabolism of galactose in the budding yeast Saccharomyces cerevisiae. Since the discovery of Gal4p, many other zinc cluster proteins have been characterized; they function in a wide range of processes, including primary and secondary metabolism and meiosis. Other roles include regulation of genes involved in the stress response as well as pleiotropic drug resistance, as demonstrated in budding yeast and in human fungal pathogens. With the number of characterized zinc cluster proteins growing rapidly, it is becoming more and more apparent that they are important regulators of fungal physiology.
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PMID:A fungal family of transcriptional regulators: the zinc cluster proteins. 1695 62

Osteoblasts and chondrocytes, which derive from a common mesenchymal precursor (osteochondroprogenitor), are involved in bone formation and remodeling in vivo. Determination of osteochondroprogenitor fate is under the control of complex hormonal and local factors converging onto a series of temporospatial dependent transcription regulators. Sox9, together with L-Sox5 and Sox6, of the Sox family is required for chondrogenic differentiation commitment, while Runx2/Cbfa 1, a member of runt family and Osterix/Osx, a novel zinc finger-containing transcription factor play a pivotal role in osteoblast differentiation decision and hypertrophic chondrocyte maturation. Recent in vitro and in vivo evidence suggests beta-catenin, a transcriptional activator in the canonical Wnt pathway, can act as a determinant factor for controlling chondrocyte and osteoblast differentiation. Here we focus on several intensively studied transcription factors and Wnt/beta-catenin signal molecules to illustrate the regulatory mechanism in directing commitment between osteoblast and chondrocyte, which will eventually allow us to properly manipulate the mesenchymal progenitor cell differentiation on bone and regeneration of cartilage tissue engineering.
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PMID:Molecular mechanism of osteochondroprogenitor fate determination during bone formation. 1712 Aug

FLOWERING LOCUS C (FLC), a strong floral repressor, is one of the central regulators of flowering in Arabidopsis thaliana. The expression of FLC is increased by FRIGIDA (FRI) but decreased by vernalization, a long period of cold exposure that accelerates flowering. Although many aspects of FLC regulation have been reported, it is not known how FLC is transcriptionally activated by FRI at the molecular level. We isolated suppressor of FRIGIDA4 (suf4), a mutant that flowers early as a result of low FLC expression. SUF4 encodes a nuclear-localized protein with two C2H2-type zinc finger motifs and a Pro-rich domain. SUF4 protein interacts with FRI and FRIGIDA-LIKE1 (FRL1), two genes for which single mutations have the same phenotype as suf4. SUF4 also bound to the promoter of FLC in a chromatin immunoprecipitation assay, suggesting that SUF4 acts as a transcriptional activator of FLC after forming a complex with FRI and FRL1. In addition, suf4 suppresses luminidependens (ld), a late-flowering mutation that causes an increase of FLC, and SUF4 protein directly interacts with LD. Thus, we propose that LD binds to SUF4 to suppress its activity in the absence of FRI.
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PMID:SUPPRESSOR OF FRIGIDA4, encoding a C2H2-Type zinc finger protein, represses flowering by transcriptional activation of Arabidopsis FLOWERING LOCUS C. 1713 94

The ZFHD recognition sequence (ZFHDRS) and NAC recognition sequence (NACRS) play an important role in the dehydration-inducible expression of the Arabidopsisthaliana EARLY RESPONSIVETO DEHYDRATION STRESS 1 (ERD1) gene. Using the yeast one-hybrid system, we isolated a cDNA encoding the ZFHD1 transcriptional activator that specifically binds to the 62 bp promoter region of ERD1, which contains the ZFHDRS. Both in vitro and in vivo analyses confirmed specific binding of the ZFHD1 to ZFHDRS, and the expression of ZFHD1 was induced by drought, high salinity and abscisic acid. The DNA-binding and activation domains of ZFHD1 were localized on the C-terminal homeodomain and N-terminal zinc finger domain, respectively. Microarray analysis of transgenic plants over-expressing ZFHD1 revealed that several stress-inducible genes were upregulated in the transgenic plants. Transgenic plants exhibited a smaller morphological phenotype and had a significant improvement of drought stress tolerance. Using the yeast two-hybrid system, we detected an interaction between ZFHD1 and NACRS-binding NAC proteins. Moreover, co-over-expression of the ZFHD1 and NAC genes restored the morphological phenotype of the transgenic plants to a near wild-type state and enhanced expression of ERD1 in both Arabidopsis T87 protoplasts and transgenic Arabidopsis plants.
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PMID:Co-expression of the stress-inducible zinc finger homeodomain ZFHD1 and NAC transcription factors enhances expression of the ERD1 gene in Arabidopsis. 1723 95

Jumonij (JMJ)/Jarid2 plays important roles in embryonic development and functions as a transcriptional repressor. Using yeast two-hybrid screening, we have identified a cofactor of JMJ, the zinc finger protein 496 (Zfp496) that contains a SCAN, KRAB and zinc finger domain. Our molecular analyses indicate that Zfp496 functions as a transcriptional activator. Further, Zfp496 inhibits the transcriptional repression of JMJ and JMJ represses the transcriptional activation of Zfp496. This study demonstrates that JMJ physically and functionally interacts with Zfp496, which will provide important insights into endogenous target gene regulation by both factors.
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PMID:Characterization of zinc finger protein 496 that interacts with Jumonji/Jarid2. 1752 33

The DNA genomes of geminiviruses have a limited coding capacity that is compensated for by the production of small multifunctional proteins. The AL2 protein encoded by members of the genus Begomovirus (e.g., Tomato golden mosaic virus) is a transcriptional activator, a silencing suppressor, and a suppressor of a basal defense. The related L2 protein of Beet curly top virus (genus Curtovirus) shares the pathogenicity functions of AL2 but lacks transcriptional activation activity. It is known that AL2 and L2 can suppress local silencing by interacting with adenosine kinase (ADK) and can suppress basal defense by interacting with SNF1 kinase. However, how the activities of these viral proteins are regulated remains an unanswered question. Here, we provide some answers by demonstrating that AL2, but not L2, interacts with itself. The zinc finger-like motif (CCHC) is required but is not sufficient for AL2 self-interaction. Alanine substitutions for the invariant cysteine residues that comprise the motif abolish self-interaction or cause aberrant subnuclear localization but do not abolish interaction with ADK and SNF1. Using bimolecular fluorescence complementation, we show that AL2:AL2 complexes accumulate primarily in the nucleus, whereas AL2:ADK and L2:ADK complexes accumulate mainly in the cytoplasm. Further, the cysteine residue mutations impair the ability of AL2 to activate the coat protein promoter but do not affect local silencing suppression. Thus, AL2 self-interaction correlates with nuclear localization and efficient activation of transcription, whereas AL2 and L2 monomers can suppress local silencing by interacting with ADK in the cytoplasm.
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PMID:Functional modulation of the geminivirus AL2 transcription factor and silencing suppressor by self-interaction. 1771 41

The hypersensitive response (HR) is a common feature of plant disease resistance reactions and a type of programmed cell death (PCD). Many pathogens are able to modulate pathways involved in cell death. In contrast to animal viruses, inhibitors of PCD activity have not been identified for plant-infecting viruses. Previously, we have reported that the nuclear shuttle protein (NSP) of Tomato leaf curl New Delhi virus (ToLCNDV) induces an HR in Nicotiana tabacum and Lycopersicon esculentum plants when expressed under the control of the Cauliflower mosaic virus 35S promoter. However, HR is not evident in plants infected with ToLCNDV, suggesting that the virus encodes a factor (or factors) that counters this response. Analysis of all ToLCNDV-encoded genes pinpointed the transcriptional activator protein (TrAP) as the factor mediating the anti-HR effect. Deletion mutagenesis showed the central region of TrAP, containing a zinc finger domain and nuclear localization signal, to be important in inhibiting the HR. These results demonstrate that TrAP counters HR-induced cell death, the first such activity identified for a plant-infecting virus.
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PMID:The hypersensitive response to tomato leaf curl New Delhi virus nuclear shuttle protein is inhibited by transcriptional activator protein. 1799 Sep 65

GATA3, a transcriptional activator, plays a critical role in the development of T-cells and differentiation to T helper type 2 cells. To date, no information is available on the role of GATA3 in the teleost immune system. We identified full-length cDNA and alternatively spliced variants of ginbuna crucian carp GATA3 (gbGATA3). The gbGATA3 gene is transcribed into multiple splice variants lacking either one or both zinc finger domains, although the sequences of both domains are fully conserved between ginbuna and other vertebrates. We found that alternative splice site and stop codon in gbGATA3 intron 3, located between exons that separately encode the two zinc finger domains, are conserved among teleosts, suggesting that teleost GATA3 gene can be translated into multiple isoforms. RT-PCR analysis revealed that the gbGATA3 is strongly expressed in the brain, thymus and gill of unstimulated fish. Moreover, gbGATA3 expression was detected in surface-IgM-negative lymphocytes among kidney cells sorted by FACS. Real-time PCR demonstrated that expression levels of full-length gbGATA3 and the splice variants differed with tissue type, but full length was always the predominantly expressed form. These results suggest that gbGATA3, including its splice variants, is involved in teleost T-cell function.
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PMID:GATA3 mRNA in ginbuna crucian carp (Carassius auratus langsdorfii): cDNA cloning, splice variants and expression analysis. 1831 40

Duchenne muscular dystrophy is caused by a genetic defect in the dystrophin gene. The absence of dystrophin results in muscle fiber necrosis and regeneration, leading to progressive muscle fiber loss. Utrophin is a close analogue of dystrophin. A substantial, ectopic expression of utrophin in the extrasynaptic sarcolemma of dystrophin-deficient muscle fibers can prevent deleterious effects of dystrophin deficiency. An alternative approach for the extrasynaptic up-regulation of utrophin involves the augmentation of utrophin transcription via the endogenous utrophin A promoter using custom-designed transcriptional activator proteins with zinc finger (ZFP) motifs. We tested a panel of custom-designed ZFP for their ability to activate the utrophin A promoter. Expression of one such ZFP efficiently increased, in a time-dependent manner, utrophin transcript and protein levels both in vitro and in vivo. In dystrophic mouse (mdx) muscles, administration of adenoviral vectors expressing this ZFP led to significant enhancement of muscle function with decreased necrosis, restoration of the dystrophin-associated proteins, and improved resistance to eccentric contractions. These studies provide evidence that specifically designed ZFPs can act as strong transcriptional activators of the utrophin A promoter. These may thus serve as attractive therapeutic agents for dystrophin deficiency states such as Duchenne muscular dystrophy.
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PMID:Targeting artificial transcription factors to the utrophin A promoter: effects on dystrophic pathology and muscle function. 1894 75


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