17beta-estradiol (E2) induces cdc25A gene expression in breast cancer cells by genomic and non-genomic pathways.
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.
Ru Lee
Wan
W
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466, USA.
Chen
Chien-Cheng
CC
Liu
Shengxi
S
Safe
Stephen
S
D001482:Base Composition; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D035581:Transcription Factor TFIIB / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D023081:CCAAT-Binding Factor; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D047628:Estrogen Receptor alpha; C116359:NFYA protein, Xenopus; D016160:Retinoblastoma Protein; D016329:Sp1 Transcription Factor; D035581:Transcription Factor TFIIB; D014157:Transcription Factors; D029867:Xenopus Proteins; C402244:nuclear factor Y; D004958:Estradiol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases