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*ESTRADIOL
Endocrinology Vol. 142, No. 3 1000-1008
Copyright © 2001 by The Endocrine Society

ARTICLES

Transcriptional Activation of Deoxyribonucleic Acid Polymerase {alpha} Gene Expression in MCF-7 Cells by 17{beta}-Estradiol1

Ismael Samudio, Carrie Vyhlidal, Fan Wang, Matthew Stoner, Ichen Chen, Michael Kladde, Rola Barhoumi, Robert Burghardt and Stephen Safe

Department of Veterinary Physiology and Pharmacology (I.S., C.V., F.W., M.S., I.C., S.S.), Department of Biochemistry and Biophysics (I.S., C.V., M.K.), Department of Veterinary Anatomy and Public Health (R.Ba., R.Bu.), Texas A&M University, College Station, Texas 77843

Address all correspondence and requests for reprints to: Stephen H. Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466. E-mail: ssafe{at}cvm.tamu.edu

Treatment of MCF-7 human breast cancer cells with 17{beta}-estradiol (E2) results in increased DNA synthesis and cell proliferation and enhanced enzyme activities associated with purine/pyrimidine biosynthesis. The mechanism of enhanced DNA polymerase {alpha} activity was investigated by analysis of the promoter region of this gene. E2 induced luciferase (reporter gene) activity in MCF-7 cells transfected with pDNAP1, pDNAP2, and pDNAP3 containing -1515 to +45, -248 to +45 and -116 to +45 inserts from the DNA polymerase {alpha} gene promoter, whereas no induction was observed with pDNAP4 (-65 to +45 insert). The induction response was dependent on cotransfection with estrogen receptor {alpha} (ER{alpha}), and transactivation was also observed with a mutant ER{alpha} that did not express the DNA-binding domain. Subsequent functional, DNA binding, and DNA footprinting studies showed that a GC-rich region at -106 to -100 was required for E2-mediated transactivation, and Sp1 protein, but not ER{alpha}, bound this sequence. Transcriptional activation of DNA polymerase {alpha} by E2 is associated with ER{alpha}/Sp1 action at a proximal GC-rich promoter sequence, and this gene is among a growing list of E2-responsive genes that are induced via ER{alpha}/Sp1 protein interactions that do not require direct binding of the hormone receptor to DNA.




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