Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis

Hiroki Utsunomiya, Utsunomiya H, Cheng YH, You-Hong Cheng, Zhihong Lin, Lin Z, Reierstad S, Scott Reierstad, Ping Yin, Yin P, Attar E, Erkut Attar, Xue Q, Qing Xue, Imir G, Gonca İmir, Steven Thung, Thung S, Elena Trukhacheva, Trukhacheva E, Takashi Suzuki, Suzuki T, Sasano H, Hironobu Sasano, Julie Kim, J Julie Kim, Nobuo Yaegashi, Yaegashi N, Bulun Se, Serdar E. Bulun
Molecular Endocrinology · 2007 · vol. 22(4) , pp. 904–914 · doi:10.1210/me.2006-0302 · PMID:18165439 · PMC2276471 · W1964803062
Lab / animal OA: bronze CC0 ⤵ 40 in-corpus citations
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Upstream stimulatory factor-2 (USF2) is elevated in endometriotic stromal cells, leading to increased steroidogenic factor-1 (SF-1) expression and subsequently up-regulating StAR and aromatase, contributing to higher estrogen production.

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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.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Gene Expression Gene Expression Steroidogenic Factor 1 Upstream Stimulatory Factors Aromatase Aromatase Aromatase Aromatase Cells, Cultured Cells, Cultured Chromatin Immunoprecipitation Chromatin Immunoprecipitation Endometriosis Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium

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