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Title: FUNCATIONAL INTERACTION BETWEEN LIGAND-ACTIVATED ESTROGEN RECEPTOR (ER)-ALPHA AND THE TRANSCRIPTION FACTOR BTEB1 IN UTERINE CELLS

Author
item MCQUOWN, JENNELLE
item OH, S
item SIMMEN, ROSALIA

Submitted to: Society for the Study of Reproduction Annual Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 5/31/2003
Publication Date: 7/28/2003
Citation: MCQUOWN, J.R., OH, S.P., SIMMEN, R.C. FUNCATIONAL INTERACTION BETWEEN LIGAND-ACTIVATED ESTROGEN RECEPTOR (ER)-ALPHA AND THE TRANSCRIPTION FACTOR BTEB1 IN UTERINE CELLS. SOCIETY FOR THE STUDY OF REPRODUCTION ANNUAL MEETING. 2002. v. 66(S1): Abstract p. 243.

Interpretive Summary: The hormones estrogen and progesterone are very important for female fertility. One way that these hormones act is by causing the female's uterus to become competent to accept and nurture the newly fertilized embryo. In this study, we examined if these hormones act on specific proteins to favor functioning of the uterus to allow for successful pregnancy. Indeed, our results demonstrated that one class of protein in the uterus, termed BTEB1, is itself controlled by steroid hormones and that this control is likely to be important to successful female reproduction. This research is important since it now provides an avenue to further understand how steroid hormones work to favor embryo development and how this is affected by the relative nutritional state of the individual.

Technical Abstract: Basic Transcription Element Binding (BTEB1) protein is a uterine transcription factor belonging to the KrÜppel-like family (KLF) of GC-binding proteins. We have previously shown BTEB1 to functionally interact with the progesterone receptor (PR) to increase P-sensitivity of target genes. Since the uterus is also a target of estrogen (E) action, we determined: 1) if E affects BTEB1 gene expression, and 2) if ligand-bound ER' functionally interacts with BTEB1. The human endometrial carcinoma cell line, Ishikawa, was treated with 17ß-estradiol or a synthetic progestin R5020 (10 or 100 nM each) in charcoal-stripped serum-containing medium for 24 h, and BTEB1 expression was assessed by Northern blot analysis using a human BTEB1 cDNA probe. Ovariectomized (ovx) mice were also administered E (0.1 'g/mouse) or P (1 mg/mouse) daily for 4 days, and uterine BTEB1 expression was determined by Western blot analysis using an anti-rat BTEB1 polyclonal antibody. In Ishikawa cells, E or P did not alter basal levels of BTEB1 mRNA, albeit those of the E-regulated gene, cyclin D1, were increased with E-treatment. In ovx mice, E but not P caused a modest but significant increase in uterine BTEB1 protein levels. The specificity of the E effect was demonstrated by the absence of a similar induction by E of the uterine expression of another KLF family member Sp1. Transient transfection studies in Ishikawa cells were used to evaluate if the transcriptional activity of activated ER' is modulated by BTEB1. Expression constructs for rat BTEB1 and human ER' were co-transfected with two E-responsive promoters, 4X-ERE-TK-Luc and 4X-ERE-TATA-Luc in the presence or absence of E (100 nM). Luciferase activity was stimulated in an E-dependent manner when driven by either promoter in the presence of ER' expression construct, while BTEB1 had no effect on either promoter activity in the presence or absence of E. Co-expression of BTEB1 and ER', however, inhibited the E-dependent ER' induction of both constructs. These results suggest that E may regulate uterine expression of BTEB1, which can in turn, interfere with the transcriptional activity of E-bound ER'. The significance of these findings on pregnancy events is the subject of ongoing studies.