Abstract
Cdc25A is a potent tyrosine phosphatase that catalyzes specific dephosphorylation of cyclin/cyclin-dependent kinase (cdk) complexes to regulate G1 to S-phase cell cycle progression. Cdc25A mRNA levels are induced by 17beta-estradiol (E2) in ZR-75 breast cancer cells, and deletion analysis of the cdc25A promoter identified the -151 to -12 region as the minimal E2-responsive sequence. Subsequent mutation/deletion analysis showed that at least three different cis-elements were involved in activation of cdc25A by E2, namely, GC-rich Sp1 binding sites, CCAAT motifs that bind NF-Y, and E2F sites that bind DP/E2F1 proteins. Studies with inhibitors and dominant negative expression plasmids show that E2 activates cdc25A expression through activation of genomic ERalpha/Sp1 and E2F1 and cAMP-dependent activation of NF-YA. Thus, both genomic and non-genomic pathways of estrogen action are involved in induction of cdc25A in breast cancer cells.
MeSH terms
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Base Composition
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Binding Sites
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics*
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CCAAT-Binding Factor / genetics
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CCAAT-Binding Factor / metabolism
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism
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E2F1 Transcription Factor / genetics
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E2F1 Transcription Factor / metabolism
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Estradiol / metabolism
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Estradiol / pharmacology*
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Mutation
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Promoter Regions, Genetic
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Response Elements
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Retinoblastoma Protein / metabolism
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Signal Transduction
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Sp1 Transcription Factor / genetics
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Sp1 Transcription Factor / metabolism
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Transcription Factor TFIIB / genetics
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Transcription Factor TFIIB / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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Xenopus Proteins / genetics
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Xenopus Proteins / metabolism
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cdc25 Phosphatases / drug effects
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cdc25 Phosphatases / genetics*
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cdc25 Phosphatases / metabolism
Substances
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CCAAT-Binding Factor
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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Estrogen Receptor alpha
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NFYA protein, Xenopus
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Retinoblastoma Protein
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Sp1 Transcription Factor
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Transcription Factor TFIIB
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Transcription Factors
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Xenopus Proteins
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nuclear factor Y
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Estradiol
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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CDC25A protein, human
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cdc25 Phosphatases