Role of a Proximal NF-Y Binding Promoter Element in S Phase-specific Expression of Mouse Ribonucleotide Reductase R2 Gene

Filatov, Dmitri; Thelander, Lars

doi:10.1074/jbc.270.42.25239

Cited by 41 publications

(37 citation statements)

References 24 publications

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“…Several of these genes are involved in cellular regulation, such as those for human thymidine kinase, IL-4, fibroblast growth factor-4, and ribonucleotide reductase R2 (13,14,21,32,49). NF-Y binding sites have also been reported in the cell cycle regulators CDC25C and CDC2 (15,93) both of which are important for progression through G 2 /M.…”

Section: Discussionmentioning

confidence: 99%

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Pise-Masison

Dittmer

Clemens

et al. 1997

Molecular and Cellular Biology

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Human T-cell lymphotrophic virus type 1 (HTLV-1) is the causative agent of the aggressive, usually fatal adult T-cell leukemia (see references 22, 23, 48 and 86 and references therein). Recent reports have linked HTLV-1 with additional and clinically diverse human diseases (31,46,53,59,63,65). The best characterized of these is a progressive demyelinating syndrome termed HTLV-1-associated myelopathy (HAM) or tropical spastic paraparesis (TSP) (see references 22, 23, 48, and 86 and references therein). Because of the long incubation period between viral exposure and disease onset, the mechanism of HTLV-1 pathogenesis is still unclear. It is clear that host cell control of HTLV-1 replication is a primary determinant of virus expression and subsequent disease. Studies on the variation of viral sequences among different infected groups have not revealed any particular determinant which distinguishes onset of a particular HTLV-1 associated disease (18,44,60,74,87,88).In vitro, HTLV-1 has been shown to activate and immortalize human T lymphocytes, resulting in the polyclonal proliferation of infected cells and subsequent oligoclonal or monoclonal growth (26, 43). HTLV-1 contains no known cellular protooncogene, and because there is no preferential site of integration among infected individuals, it is unlikely that insertional mutagenesis is responsible for viral transformation. Several lines of evidence suggest that the viral transcriptional activator Tax contributes to the development of disease (23,28,29,82).Tax, which is essential for viral replication (22,23,48,86), has recently been shown to transform established rodent fibroblasts to anchorage-independent growth (77, 82, 85). Moreover, Tax can transform primary rat embryo fibroblasts in cooperation with activated ras (67) as well as immortalize normal human T lymphocytes when expressed from a herpes simplex virus-based vector (28,29). Finally, transgenic mice carrying the Tax gene frequently develop mesenchymal tumors and neurofibromas (34, 62). These findings suggest that Tax plays a critical role in HTLV-1-associated leukemogenesis.Tax is believed to exert its effect by stimulating viral gene expression and by deregulating expression of cellular genes (22,23,48,86). Tax has been shown to activate transcription of a number of cellular genes involved in cell proliferation, such as those for interleukin-3 (IL-3), IL-2, the IL-2 receptor, granulocyte-macrophage colony-stimulating factor, c-Fos, c-Jun, parathyroid-related protein, and the major histocompatibility complex (MHC) class I (see references 22, 23, 48, and 86 and references therein). The aberrant expression of these growthrelated genes has been implicated in contributing to the establishment of HTLV-1-associated pathogenesis. While Tax does not bind DNA directly, it appears to stimulate RNA synthesis through protein-protein interactions with host cell transcription factors. The most well studied of these interactions is with the ATF/CREB family of transcription factors, which bind to cyclic AMP-responsive...

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Section: Discussionmentioning

confidence: 99%

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Pise-Masison

Dittmer

Clemens

et al. 1997

Molecular and Cellular Biology

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“…The region closest to the transcription start binds the NF-Y transcription factor and is required for basal transcription; the other three regions located farther upstream are required for proliferation-specific induction (121). Early during G 1 , mRNA synthesis is initiated but blocked in the first intron by a unique cell cycle-dependent transcriptional block (122).…”

Section: Eukaryotesmentioning

confidence: 99%

Ribonucleotide Reductases

Jordan

Reichard

1998

Annu. Rev. Biochem.

670

639

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Ribonucleotide reductases provide the building blocks for DNA replication in all living cells. Three different classes of enzymes use protein free radicals to activate the substrate. Aerobic class I enzymes generate a tyrosyl radical with an ironoxygen center and dioxygen, class II enzymes employ adenosylcobalamin, and the anaerobic class III enzymes generate a glycyl radical from S-adenosylmethionine and an iron-sulfur cluster. The X-ray structure of the class I Escherichia coli enzyme, including forms that bind substrate and allosteric effectors, confirms previous models of catalytic and allosteric mechanisms. This structure suggests considerable mobility of the protein during catalysis and, together with experiments involving site-directed mutants, suggests a mechanism for radical transfer from one subunit to the other. Despite large differences between the classes, common catalytic and allosteric mechanisms, as well as retention of critical residues in the protein sequence, suggest a similar tertiary structure and a common origin during evolution. One puzzling aspect is that some organisms contain the genes for several different reductases. CONTENTS

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“…The tobacco RNR2 promoter contained E2F-like motifs, similar to several animal genes induced from mid-G1 to S phase (Slansky and Farnham, 1996a), but in contrast to the animal RNR promoters, which do not possess E2F cis elements (Filatov and Thelander, 1995). The E2F motifs of the tobacco RNR2 promoter consisted in a simple element called E2Fa and a composite element consisting of a reverse E2Fb motif overlapping a CDE-CHR site.…”

Section: Singular Structure Of a Plant Rnr2 Promotermentioning

confidence: 99%

Cell Cycle Regulation of the Tobacco Ribonucleotide Reductase Small Subunit Gene Is Mediated by E2F-like Elements

et al. 2000

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Ribonucleotide reductase (RNR) is a key enzyme involved in the DNA synthesis pathway. The RNR-encoded genes are cell cycle regulated and specifically expressed in S phase. The promoter of the RNR2 gene encoding for the small subunit was isolated from tobacco. Both in vivo and in vitro studies of the DNA-protein interactions in synchronized BY2 tobacco cells showed that two E2F-like motifs were involved in multiple specific complexes, some of which displayed cell cycle-regulated binding activities. Moreover, these two elements could specifically interact with a purified tobacco E2F protein. Involvement of the E2F elements in regulating the RNR2 promoter was checked by functional analyses in synchronized transgenic BY2 cells transformed with various RNR2 promoter constructs fused to the luciferase reporter gene. The two E2F elements were involved in upregulation of the promoter at the G1/S transition and mutation of both elements prevented any significant induction of the RNR promoter. In addition, one of the E2F elements sharing homology with the animal E2F/cell cycle-dependent element motif behaved like a repressor when outside of the S phase. These data provide evidence that E2F elements play a crucial role in cell cycle regulation of gene transcription in plants. INTRODUCTIONThe G1/S transition of the cell cycle is a crucial step before entry into the S phase, in which DNA replication takes place (Johnson, 1992). One of the key processes in this phase is the biosynthesis of deoxyribonucleotides. Ribonucleotide reductase (RNR) is an essential enzyme for de novo synthesis of deoxyribonucleotides, catalyzing the reduction of the four ribonucleotide diphosphates to their corresponding deoxyribonucleotides (Reichard, 1988). The active enzyme consists of two different homodimeric subunits: the R1 large subunit, involved in the allosteric regulation of the enzyme, and the R2 small subunit, involved in the catalytic activity (Thelander et al., 1980). In yeast and mammals, both RNR activity and RNR gene expression are tightly regulated throughout the cell cycle, with maximal values in the S phase (Elledge et al., 1992;Greenberg and Hilfinger, 1996). In yeast, regulation of RNR gene expression has been studied mainly at the transcriptional level. Periodic RNR1 gene expression was suggested to be controlled by GC-rich Mlu I boxes (Elledge et al., 1992;Lowndes et al., 1992), which apparently also mediate transcription of several other S phase-specific yeast genes (Verma et al., 1991). One near-match Mlu I sequence was found on the RNR2 promoter (Elledge and Davis, 1987), but its role remains unclear. In mammals, for example, two broad regions that interact with nuclear proteins were necessary for upregulation of the mouse RNR1 promoter at the G1/S transition (Johansson et al., 1995). Surprisingly, the mouse RNR2 promoter was activated at an earlier stage, when quiescent cells started to proliferate, and three regions were involved in this activation (Filatov and Thelander, 1995). However, S phase-specific expression was a...

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Role of a Proximal NF-Y Binding Promoter Element in S Phase-specific Expression of Mouse Ribonucleotide Reductase R2 Gene

Cited by 41 publications

References 24 publications

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Ribonucleotide Reductases

Cell Cycle Regulation of the Tobacco Ribonucleotide Reductase Small Subunit Gene Is Mediated by E2F-like Elements

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Role of a Proximal NF-Y Binding Promoter Element in S Phase-specific Expression of Mouse Ribonucleotide Reductase R2 Gene

Cited by 41 publications

References 24 publications

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax1 Protein and the CCAAT Binding Protein NF-Y

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax1 Protein and the CCAAT Binding Protein NF-Y

Ribonucleotide Reductases

Cell Cycle Regulation of the Tobacco Ribonucleotide Reductase Small Subunit Gene Is Mediated by E2F-like Elements

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Product

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Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y