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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0134v1 200/1/85    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rotinen, M. Articles by Villar, J. Search for Related Content PubMed PubMed Citation Articles by Rotinen, M. Articles by Villar, J.

M Rotinen, Department of Health Sciences, Universidad Publica de Navarra, Pamplona, Spain
J Celay, Department of Health Sciences, Universidad Publica de Navarra, Pamplona, Spain
M Alonso, Neuro-oncology, MD anderson Cancer Center, Houston, United States
A Arrazola, Department of Health Sciences, Universidad Publica de Navarra, Pamplona, Spain
I Encio, Department of Health Sciences, Universidad Publica de Navarra, Pamplona, Spain
J Villar, Radiation Medicine, Georgetown University, Washington, 20057-1482, United States

Correspondence: Joaquin Villar, Email: villarj{at}mail.nih.gov

Abstract

17β-hydroxysteroid dehydrogenases (17β-HSD) are the enzymes responsible for the reversible interconversion of 17-hydroxy and 17-keto steroids. The human and mouse type 8 17β-HSD (17β-HSD8) selectively catalyze the conversion of estradiol (E2) to estrone (E1). We previously described that 17β-HSD8 is transcriptionally regulated by C/EBPβ, and that C/EBPβ is bound to CCAAT boxes located at -5 and -46 of the transcription start site in basal conditions in HepG2 cells. Furthermore, ectopic expression of C/EBPβ transactivated the 17β-HSD8 promoter activity. Here, we show that 17β-HSD8 expression is up-regulated in response to E2 in the Estrogen Receptor alpha (ER) positive MCF-7 cells. Results showed that this induction is mediated by ER because (i) E2 did not induced 17β-HSD8 expression in ER negative HepG2 cells,(ii) ectopic expression of ER restored E2-induced 17β-HSD8 expression, and (iii) this induction was blocked by the anti-estrogen receptor ICI 182,780. Additional experiments showed that no estrogen response element (ERE) was necessary for this regulation. However, the CCAAT boxes located at the 17β-HSD8 proximal promoter were required for E2-induced transcription. Furthermore, co-immunoprecipitation studies revealed tethering of ER to C/EBPβ in response to E2 in cells expressing ER. Additionally, chromatin immunoprecipitation assays demonstrated that, in response to E2, ER is recruited to the CCAAT boxes in which C/EBPβ is already bound. Taken together, our results reveal that ER is involved in the transcriptional regulation of 17β-HSD8 gene in response to E2 through its interaction with C/EBPβ.