Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis
Open accessAbstract
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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References 37 · Cited by 72
- Authors
- Utsunomiya, H., Cheng, Y.-H., Lin, Z., Reierstad, S., Yin, P., Attar, E., Xue, Q., Imir, G., Thung, S., Trukhacheva, E., Suzuki, T., Sasano, H., Kim, J. J., Yaegashi, N., & Bulun, S. E.
- Affiliations
- Northwestern University (US)
- Division of Reproductive Biology Research (H.U., Y.-H.C., Z.L., S.R., P.Y., E.A., Q.X., G.I., S.T., E.T., J.J.K., S.E.B.), Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Illinois 60611
- Departments of Pathology (T.S., H.S.), 980-8574 Sendai, Japan
- Tohoku University (JP)
- Corresponding author
- Bulun, Serdar E.
- ORCID
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-04-01
- Volume
- 22
- Issue
- 4
- Pages
- 904-914
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC2276471
- OpenAlex
- W1964803062
- Cited by
- 72
- References
- 37
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 5 · 2022: 2 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 6 · 2012: 7
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Avon Foundation for Women
- Northwestern University
- National Institutes of Health
- Feinberg School of Medicine
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD044715, HD38961)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- endometriosis, steroidogenic factor 1, upstream stimulatory factor 1, steroidogenic acute regulatory protein, aromatase, estrogen synthesis, E-box, transcriptional regulation, endometriotic stromal cells, promoter regulation
- MeSH terms
- Aromatase, Cells, Cultured, Endometriosis, Endometrium, Female, Humans, Immunohistochemistry, Promoter Regions, Genetic, RNA, Messenger, Transcription, Genetic, Transfection, Immunoblotting, Gene Expression, Stromal Cells, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Chromatin Immunoprecipitation, Upstream Stimulatory Factors, Steroidogenic Factor 1
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