Clone pAT 133 identifies a gene that encodes another human member of a class of growth factor-induced genes with almost identical zinc-finger domains.
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We report the structure and regulation of a gene represented by clone pAT 133, which is induced upon transition from a resting state (G0) through the early phase of the cell cycle (G1). The pAT 133 gene is immediately induced, with FOS-like kinetics, in human T cells and in fibroblasts. Primary structure analysis showed that the encoded protein contains three tandem zinc-finger sequences of the type Cys2-Xaa12-His2. This zinc-finger region, which is thought to bind DNA in a sequence-specific manner, is similar (greater than 80% on the amino acid level) to two previously described transcription factors pAT 225/EGR1 and pAT 591/EGR2. Except for the conserved zinc-finger domains, the amino acid sequences of the three proteins are distinct. This structural similarity suggests that the pAT 133 gene encodes a transcription factor with a specific biological function. Comparing the regulation of these related zinc-finger-encoding genes showed coordinate induction upon mitogenic stimulation of resting T lymphocytes and of resting fibroblasts. However, upon transition from a proliferating (G1) to a resting state of the cell cycle the three genes were differently regulated. In human histiocytic U937 cells mRNA of clone pAT 133 was constitutively expressed, whereas mRNA of pAT 225/EGR1 was induced upon induction of terminal differentiation. In contrast mRNA representing pAT 591/EGR2 was not expressed in these cells. This difference in gene regulation suggests distinct biological roles in the control of cell proliferation for the respective proteins.Keywords:
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Thenervegrowth factor-induced clone C (NGFI-C) geneencodes azinc-finger transcription factor that israpidly induced bynerve growth factor inratpheochromo- cytoma PC12cells andbyseizure inbrain. NGFI-Cisclosely related tothepreviously described early response genes, nerve growth factor-induced clone A(NGFI-A orEGRi), EGR2,and EGR3.These four early response (immediate early) proteins all contain verysimilar zinc-finger DNA binding domains; in addition, analysis ofthenon-zinc-finger region revealed that they share anadditional five highly homologous subdomains, fourofwhicharewithin theaminoterminus. The5'flanking region ofNGFI-Ccontains several cAMPresponse elements butdoesnotcontain anyserum-response elements orCArG boxes (CC(A/T)6GG), cis-acting elements commonly involved inearly response generegulation. NGFI-CmRNAwasdetected inneural tissues ofpostnatal animals, butnoexpression was found inratembryos. Insitu hybridization demonstrated that NGFI-Cisrapidly induced inthedentate gyros ofthehippo- campus after seizure, butincontrast toNGFI-A, increases in NGFI-CmRNA werenotdetected intheoverlying cortex. By using fluorescence insitu hybridization, NGFI-Cwaslocalized tohumanchromosome 2pl3. Thisregion contains aconstitu- tive fragile site thatisassociated withchromosomal break- points andtranslocations characteristic ofsomechronic lym- phocytic leukemias. Wheneukaryotic cells arestimulated toundergo mitogenesis ordifferentiation, theexpression ofasmall subset ofgenes, termed early response orimmediate early genes (1), israpidly activated. Manyearly response genes encode transcriptional regulators (2,3),forexample nervegrowth factor-induced clones CandA (NGFI-C andNGFI-A(also called EGRIand zif268, respectively)), Krox-20/EGR2, andEGR3,encode transcription factors whoseDNA-binding domains arehighly related. Thesedomains consist ofthree zincfingers and recognize theDNA element GCGGGGGCG(4)fromwhich eachofthese proteins iscapable ofactivating transcription (4-6). TheNGFI-CcDNA wasoriginally isolated fromnerve growthfactor (NGF)-stimulated ratpheochromocytoma PC12cells byusing degenerate probes corresponding tothe zinc-finger region (7). RNA blotanalysis showedthat NGFI-Cwasrapidly activated inPC12cells treated with NGFandbyseizure inratbrain. Wenowreport theisolation andnucleotide sequence oftheratNGFI-Cgene,¶ which is structurally similar totheNGFI-A, EGR2(the humanho- molog ofKrox-20), andEGR3loci. Analysis oftheamino acid sequences ofthese four proteins revealed that they share five regions ofhomology inaddition totheir DNA-binding do- mains. Atbirth noNGFI-Cexpression wasdetected inthe rat, butNGFI-CmRNA levels increase gradually during the first 3weeksoflife, plateauing atalevel similar tothat observed intheadult. Intheadult rat, NGFI-Cexpression is restricted tothebrain andother neural tissues. Likeother early response genes, NGFI-Cexpression wasdetected primarily inthedentate gyrusafter aseizure induced by electroconvulsive treatment (ECT).Chromosomal insitu hybridization wasusedtodemonstrate thatNGFI-Cislo- cated athumanchromosome 2pl3, aregion involved ina variant ofchronic lymphocytic leukemia. METHODS
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The design of novel genes encoding artificial transcription factors represents a powerful tool in biotechnology and medicine. We have engineered a new zinc finger‐based transcription factor, named Blues, able to bind and possibly to modify the expression of fibroblast growth factor 4 (FGF‐4, K‐fgf), originally identified as an oncogene. Blues encodes a three zinc finger peptide and was constructed to target the 9 bp DNA sequence: 5′‐GTT‐TGG‐ATG‐3′, internal to the murine FGF‐4 enhancer, in proximity of Sox‐2 and Oct‐3 DNA binding sites. Our final aim is to generate a model system based on artificial zinc finger genes to study the biological role of FGF‐4 during development and tumorigenesis.
Zinc finger nuclease
Sp1 transcription factor
Krüppel
GATA4
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A number of transcription factors contain so‐called zinc finger domains for the interaction with their cognate DNA sequence. It has been shown that removal of the zinc ions complexed in these zinc fingers abrogates DNA binding and transcription activation. Therefore we wanted to test the hypothesis that the activity of transcription factors could be regulated by physiological chelators of zinc. A prominent candidate for such a chelator is the Cys‐rich protein thionein (apometallothionein) that is inducible by heavy metal loads, and by other environmental stimuli. Here we show with DNA binding and in vitro transcriptions assays that thionein indeed can inactive the zinc finger‐containing Spl in a reversible manner. By contrast, transcription factor Oct‐l, which binds DNA via a homeo‐domain, i.e. a helix‐turn‐helix motif not involving zinc ions, is refractory to thionein action. We propose that modulation of intracellular thionein concentration is used for the coordinated regulation of a large subset of genes whose transcription depends on zinc finger proteins.
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Sp1 transcription factor
LIM domain
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Ring finger
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AbstractThe zinc finger protein NGFI-A (also called EGR1, Krox24, or zif268) is a candidate regulator of myeloid cell differentiation. Evidence supporting this hypothesis is twofold. First, NGFI-A antisense oligonucleotides prevent macrophage differentiation in HL-60 and U937 myeloid leukemia cell lines and in normal bone marrow cells. Second, enforced expression of NGFI-A blocks granulocytic differentiation and promotes macrophage differentiation in HL-60 cells and in the hematopoietic progenitor cell line 32D. We sought to determine the effect of NGFI-A deficiency on macrophage differentiation and function in vivo by examining native bone marrow cells from mice homozygous for a disrupted allele of NGFI-A derived from gene-targeted ES cells. Macrophages were observed in peripheral blood and several tissues, indicating that NGFI-A was not required for the formation of a variety of macrophage compartments. No differences in myeloid cell differentiation were observed between wild-type and NGFI-A−/− bone marrow cells cultured in the presence of macrophage, granulocyte-macrophage, or granulocyte colony-stimulating factor (M-CSF, GM-CSF, or G-CSF). Activation of NGFI-A−/− macrophages was comparable to that of wild-type macrophages as determined by nitric oxide production and increased cell surface expression of class II major histocompatibility complex molecules. Moreover, NGFI-A−/− mice showed no increased mortality or bacterial burden when challenged with Listeria mono-cytogenes. Together these results indicate that NGFI-A is not required for macrophage differentiation or activation.
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Myelopoiesis
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The nmtl' gene of the fission yeast Schizoeaccharomycee pombe is subject to transcriptional repression mediated by thiamine.The promoter of nmtl' has been used to construct a series of vectors that are now commonly used for the regulated expression of genes in S. pombe.In this report, we describe ntfl+, a gene involved in regulating nrntl+ expression.The ntfl' gene was cloned in a high copy suppressor screen that utilized a construct, nmtl:weel+, in which expression of the mitotic inhibitor Weel tyrosine kinase was placed under the control of the nmtl promoter.ntfl' encodes a 706-amino acid protein that shares substantial homology with a family of Cys, zinc finger-containing transcription factors typified by GAL4 from Saccharomycee cereviuiae.Increased gene dosage of ntfl' greatly increases both the repressed and derepressed activity of the nmtl promoter.Cells having a disrupted version of ntfl' are viable thiamine prototrophs, but basal expression from the nmtl promoter is greatly reduced.These data demonstrate that Ntfl plays an important role in regulating nmtl expression.The cell cycle of the fission yeast Schizosaccharomyces pombe is controlled at two major transitions, one in late G, phase, analogous to START in Saccharomyces cerevisiae, and the other in late G, phase, which regulates entry into mitosis (1).During exponential growth, the G,/M transition is rate-limiting and ensures that mitosis and cell division are only permitted when the cells have attained a critical mass.Since S. pombe cells grow exclusively by length extension, changes in the control coordinating cellular growth with the G,/M transition are reflected by modification of cell length at cell division.The molecular events that bring about the onset of mitosis are centered around the activation of a n evolutionarily conserved protein kinase complex that consists of a 34-kDa catalytic core and a larger regulatory subunit known as cyclin B. In S. pombe, these components are encoded by the cdc2' and cdcl3+ genes, respectively.Activation of the Cdc2/cyclin B kinase in fission yeast is grant (to P. R.).
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