Upstream Stimulatory Factor Proteins Are Major Components of the Glucose Response Complex of the L-type Pyruvate Kinase Gene Promoter

̧ois-Martinez, Anne-Marie Lefran; Martinez, Antoine; Antoine, B; Raymondjean, Michel; Kahn, Axel

doi:10.1074/jbc.270.6.2640

Cited by 106 publications

(136 citation statements)

References 20 publications

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“…The use of a dominant-negative mutant, TDUSF2a⌬B, demonstrated that functional USF2 oligomers are important for activation of the ATPA gene in vivo. This mutant protein is able to dimerize through its HLH-zip motif but cannot bind DNA because of a deletion in the basic region (9,25). Consequently, in cells transfected with the TDUSF2a⌬B mutant, functional USF2 oligomers are expected to be progressively replaced by defective oligomers unable to interact with the ATPA E-box.…”

Section: Resultsmentioning

confidence: 99%

“…These clones were plaque purified, and the nucleotide sequence of a portion of each cDNA was determined (23). Analyses of these sequences revealed that one cDNA encoded the regulatory factor, E12 (26) and the other cDNA encoded the transcription factor, USF2 (14,25). Both E12 and USF2 have been shown to bind to E-box elements and to regulate the expression of a number of genes.…”

Section: Resultsmentioning

confidence: 99%

“…USF2a Isoform Also Activates the ATPA Promoter-Alternatively spliced forms of USF2 resulting from the presence or absence of the fourth exon have been described (9,25). The previous trans-activation experiments were carried out using the USF2 isoform that lacks the fourth exon, termed USF2b.…”

Section: Resultsmentioning

confidence: 99%

“…The strategy used relied on the use of a dominant-negative mutant of USF2, TDUSF2a⌬B. This mutant lacks the basic region required for DNA binding but can still dimerize with endogenous USF1 or USF2 proteins or with itself (9,25). Since the binding of USF to cognate sites requires dimers possessing two functional DNA binding domains (13,14,28), the sequestration of endogenous USF by ectopically expressed TDUSF2a⌬B allows the identification of transcriptional processes that are directly dependent upon USF2.…”

Section: Resultsmentioning

confidence: 99%

“…The human USF1 expression vector was a kind gift from Dr. R. Roeder (24). The human USF2a and USF2b expression cDNAs (25) and the mouse wild-type USF2a, mutant USF2a⌬N, and mutant TDUSF2a⌬B expression cDNAs (9) were generous gifts from Dr. Raymondjean and Dr. Sawadogo, respectively. The E12 expression vector was generously provided by Dr. Kadesch (26).…”

Section: Materials-mentioning

confidence: 99%

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Regulation of the Nuclear Gene That Encodes the α-Subunit of the Mitochondrial F0F1-ATP Synthase Complex

Breen

Jordan

1997

Journal of Biological Chemistry

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We have previously identified several positive cis-acting regulatory regions in the promoters of the bovine and human nuclear-encoded mitochondrial F 0 F 1 -ATP synthase ␣-subunit genes (ATPA). One of these cis-acting regions contains the sequence 5 -CACGTG-3 (an Ebox), to which a number of transcription factors containing a basic helix-loop-helix motif can bind. This E-box element is required for maximum activity of the ATPA promoter in HeLa cells. The present study identifies the human transcription factor, upstream stimulatory factor 2 (USF2), as a nuclear factor that binds to the ATPA E-box and demonstrates that USF2 plays a critical role in the activation of the ATPA gene in vivo. Evidence includes the following. Antiserum directed against USF2 recognized factors present in HeLa nuclear extracts that interact with the ATPA promoter in mobility shift assays. Wild-type USF2 proteins synthesized from expression vectors trans-activated the ATPA promoter through the E-box, whereas truncated USF2 proteins devoid of the amino-terminal activation domains did not. Importantly, expression of a dominant-negative mutant of USF2 lacking the basic DNA binding domain but able to dimerize with endogenous USF proteins significantly reduced the level of activation of the ATPA promoter caused by ectopically coexpressed USF2, demonstrating the importance of endogenous USF2 in activation of the ATPA gene.Most cellular ATP is synthesized in the mitochondria through the process of oxidative phosphorylation. The mammalian mitochondrial oxidative phosphorylation system requires the functional interaction of gene products encoded by both the nuclear and the mitochondrial genomes (for reviews, see Refs. 1 and 2). The activities of the enzymes of the mammalian oxidative phosphorylation system vary greatly in response to a number of physiological conditions, including cell proliferation, hormonal stimulation, development, and differentiation (for reviews, see Refs. 3 and 4). The levels of these enzymes are controlled, at least in part, at a transcriptional level, although regulation at a post-transcriptional level also plays an important role in mitochondrial biogenesis (1-4).During the past several years, analysis of mammalian nuclear encoded oxidative phosphorylation genes has resulted in the identification of a number of regulatory factors that contribute to the transcription of these genes. Characterization of these gene regulatory mechanisms should allow the delineation of signals involved in the control of cellular energy production and, possibly, in the coordinate expression of genes encoding proteins of the oxidative phosphorylation system. Our laboratory has been analyzing the regulation of the nuclear gene that encodes the ␣-subunit of the mammalian mitochondrial F 0 F 1 -ATP synthase complex (ATPA) and has identified several positive cis-acting regulatory regions that are important for expression of this gene (5). Furthermore, we have found that protein factor(s) present in HeLa nuclei bind to these cis-acting regions. For e...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Materials-mentioning

confidence: 99%

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Regulation of the Nuclear Gene That Encodes the α-Subunit of the Mitochondrial F0F1-ATP Synthase Complex

Breen

Jordan

1997

Journal of Biological Chemistry

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PAI‐1 transcriptional regulation during the G₀ → G₁ transition in human epidermal keratinocytes

Li¹,

Allen²,

Lu³

et al. 2006

J of Cellular Biochemistry

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Plasminogen activator inhibitor type-1 (PAI-1) is the major negative regulator of the plasmin-dependent pericellular proteolytic cascade. PAI-1 gene expression is normally growth state regulated but frequently elevated in chronic fibroproliferative and neoplastic diseases affecting both stromal restructuring and cellular migratory activities. Kinetic modeling of cell cycle transit in synchronized human keratinocytes (HaCaT cells) indicated that PAI-1 transcription occurred early after serum stimulation of quiescent (G0) cells and prior to entry into a cycling G1 condition. PAI-1 repression (in G0) was associated with upstream stimulatory factor-1 (USF-1) occupancy of two consensus E box motifs (5'-CACGTG-3') at the PE1 and PE2 domains in the PF1 region (nucleotides -794 to -532) of the PAI-1 promoter. Chromatin immunoprecipitation (ChIP) analysis established that the PE1 and PE2 site E boxes were occupied by USF-1 in quiescent cells and by USF-2 in serum-activated, PAI-1-expressing keratinocytes. This reciprocal and growth state-dependent residence of USF family members (USF-1 vs. USF-2) at PE1/PE2 region chromatin characterized the G0 --> G1 transition period and the transcriptional status of the PAI-1 gene. A consensus E box motif was required for USF/E box interactions, as a CG --> AT substitution at the two central nucleotides inhibited formation of USF/probe complexes. The 5' flanking sites (AAT or AGAC) in the PE2 segment were not necessary for USF binding. USF recognition of the PE1/PE2 region E box sites required phosphorylation with several potential involved residues, including T153, maping to the USF-specific region (USR). A T153A substitution in USF-1 did not repress serum-induced PAI-1 expression whereas the T153D mutant was an effective suppressor. As anticipated from the ChIP results, transfection of wild-type USF-2 failed to inhibit PAI-1 induction. Collectively, these data suggest that USF family members are important regulators of PAI-1 gene control during serum-stimulated recruitment of quiescent human epithelial cells into the growth cycle.

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Hyperglycemia regulates MDR-1, drug accumulation and ROS levels causing increased toxicity of carboplatin and 5-fluorouracil in MCF-7 cells

2011

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There is constant increase in number of diabetic cases thereby giving it status of a serious epidemic. Diabetes increases the risk of occurrence of several cancers including breast cancer and may also have a serious impact on the outcome of cancer treatment. In the present study we investigated effect of hyperglycemia on cytotoxic efficacy of carboplatin and 5-fluorouracil in MCF-7 cells. MCF-7 cells were grown in 5.5 or 25 mM glucose chronically. We show that hyperglycemia favors proliferation of MCF-7 cells and increases expression of cell cycle regulatory proteins cyclin E and cdk-2. Hyperglycemia enhances cytotoxicity of carboplatin and 5-fluorouracil in MCF-7 cells by approximately 30% and decreases their IC50 by 1.5- and 1.3-folds, respectively. Hyperglycemia reduces expression of P-glycoprotein and promotes cell killing by increasing drug accumulation. Treatment with 40 µM verapamil, an inhibitor of P-gp activity specifically increases killing of MCF-7 cells cultured in 5.5 mM glucose. Further, this effect is synergized by elevated reactive oxygen species and treatment with N-Acetylcysteine, an inhibitor of ROS, increases survival by 30 and 18% in carboplatin- and 5-fluorouracil-treated cells cultured in high glucose, respectively. Cytotoxicity of these drugs is associated with reduced activation of Akt and decreased transcriptional activation of NF-κB. In conclusion, hyperglycemia potentiates cytotoxicity of drugs by reducing P-gp expression and, increased ROS levels may partially or completely contribute to enhanced toxicity.

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Upstream Stimulatory Factor Proteins Are Major Components of the Glucose Response Complex of the L-type Pyruvate Kinase Gene Promoter

Cited by 106 publications

References 20 publications

Regulation of the Nuclear Gene That Encodes the α-Subunit of the Mitochondrial F0F1-ATP Synthase Complex

Regulation of the Nuclear Gene That Encodes the α-Subunit of the Mitochondrial F0F1-ATP Synthase Complex

PAI‐1 transcriptional regulation during the G₀ → G₁ transition in human epidermal keratinocytes

Hyperglycemia regulates MDR-1, drug accumulation and ROS levels causing increased toxicity of carboplatin and 5-fluorouracil in MCF-7 cells

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Upstream Stimulatory Factor Proteins Are Major Components of the Glucose Response Complex of the L-type Pyruvate Kinase Gene Promoter

Cited by 106 publications

References 20 publications

Regulation of the Nuclear Gene That Encodes the α-Subunit of the Mitochondrial F0F1-ATP Synthase Complex

Regulation of the Nuclear Gene That Encodes the α-Subunit of the Mitochondrial F0F1-ATP Synthase Complex

PAI‐1 transcriptional regulation during the G0 → G1 transition in human epidermal keratinocytes

Hyperglycemia regulates MDR-1, drug accumulation and ROS levels causing increased toxicity of carboplatin and 5-fluorouracil in MCF-7 cells

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Product

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PAI‐1 transcriptional regulation during the G₀ → G₁ transition in human epidermal keratinocytes