Upstream Stimulatory Factor-2 Regulates Steroidogenic Factor-1 Expression in Endometriosis

Abstract

Local estrogen biosynthesis is a major factor in the pathogenesis of endometriosis. Aberrant expression of steroidogenic acute regulatory protein (StAR) and aromatase in endometriotic tissue leads to an up-regulation of estrogen production. The transcription factor steroidogenic factor-1 (SF-1) activates the promoters of both StAR and aromatase in endometriotic tissue. We investigated differences in SF-1 expression in endometriotic tissue and normally located endometrium to elucidate the mechanism underlying increased StAR and aromatase activities in endometriosis. Serial deletion and site-directed mutants of the SF-1 promoter showed that an E-box sequence was critical for its activity in endometriotic stromal cells. EMSAs showed that the upstream stimulatory factor (USF) 1 and 2 in nuclear extracts from endometrial and endometriotic stromal cells bound to the E-box. Chromatin-immunoprecipitation-PCR assay, however, demonstrated in intact cells that binding activity of USF2 to the SF-1 promoter was strikingly higher than that of USF1 in endometriotic stromal cells and that USF1 or USF2 binding activity was hardly detectable in endometrial stromal cells. Moreover, knockdown of USF2 but not USF1 resulted in robust and consistent down-regulation of SF-1 and its target genes StAR and aromatase in endometriotic stromal cells. USF2 but not USF1 mRNA and protein levels were significantly higher in endometriotic vs. endometrial stromal cells. In vivo, USF2 mRNA and immunoreactive USF2 levels in endometriotic tissues were strikingly higher than those in endometrium. Taken together, the elevated levels of USF2 in endometriosis account for, in part, the aberrant expression of SF-1 and its target gene StAR and aromatase.

Association between MMP1 and MMP9 activities and ICAM1 cleavage induced by tumor necrosis factor in stromal cell cultures from eutopic endometria of women with endometriosis

“…The similar results obtained in proliferative and secretory endometrial stromal cells at passages 2-3 cultured in the absence of ovarian steroids suggest the loss during culture of their characteristic regulation on endometria in vivo; then, and similarly to other authors (Vigano et al 2001, Utsunomiya et al 2008, we analyzed all data together. As it has been widely reported, the stromal cells treatment with steroids induces their differentiation to predecidual stromal cells in vitro allowing the molecule synthesis expressed during the uterine receptive window (Sugino et al 2000, White et al 2005.…”

Expression of Steroidogenic Factor 1 (SF-1) and Steroidogenic Acute Regulatory Protein (StAR) in Endometriosis is Associated with Endometriosis Severity

“…Some studies have suggested that methylation of the SF-1 promoter and the upregulation of stimulatory factor-2 might play important roles in SF-1 regulation. 18,19 To investigate the roles of SF-1 and StAR in endometriosis, any association between the expression levels of these proteins and the menstrual cycle and stage of endometriosis was evaluated. The results showed that the expression levels of SF-1 and StAR in ectopic endometria were significantly correlated with the stage of endometriosis; higher expression of SF-1 and StAR were observed in the early stages compared with the advanced stages of endometriosis.…”

In Vivo Regulation of Follicle-Stimulating Hormone Receptor by the Transcription Factors Upstream Stimulatory Factor 1 and Upstream Stimulatory Factor 2 Is Cell Specific

“…When considered together with the results of ChIP analysis, the finding suggests that reduced Fshr expression results from the direct loss of USF at the Fshr promoter. However, previous studies identify another potential mechanism involving the transcription factor SF-1 (or NR5A1), which was identified as both a target of USF and an activator of Fshr (15,(31)(32)(33). Because Sertoli cells and granulosa cells express both SF-1 and FSHR, a reduction in SF-1, due to USF loss, could be responsible for the reduction in Fshr mRNA (34,35).…”