WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells.
Abstract
The orphan nuclear receptor steroidogenic factor-1 (SF-1) induces the expression of Müllerian inhibiting substance (MIS) and many steroidogenic genes, including aromatase P450 (P450arom). Dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1) inhibits SF-1-mediated induction of MIS and other steroidogenic genes, whereas Wilms' tumor suppressor gene (WT1) augments SF-1-mediated MIS expression. The effects of WT1 on steroidogenesis or P450arom expression have not been explored to date. In human endometriotic stromal cells, extremely high levels of P450arom mRNA and enzyme activity are present. Prostaglandin E(2) stimulates cAMP formation, SF-1 binding activity, P450arom mRNA levels, and estrogen synthesis in endometriotic stromal cells. Stromal cells of eutopic endometrium from disease-free women, on other hand, do not contain readily detectable levels of P450arom mRNA. Thus, we evaluated herein the possible roles of WT1 and DAX-1 in cAMP/SF-1-mediated regulation of P450arom expression in endometriotic and endometrial stromal cells. We also determined the cellular distribution and levels of these transcription factors in pathological endometriotic vs. normal eutopic endometrial tissues by immunohistochemistry to understand their in vivo roles. In vitro transcriptional regulation studies showed that both WT1 and DAX-1 inhibited cAMP and/or SF-1-induced P450arom promoter activity in a dose-dependent fashion in cultured human endometriotic and endometrial stromal cells. Site-directed disruption of the SF-1 binding site (-136/-124 bp) in the P450arom promoter abolished basal or cAMP/SF-1-induced promoter activity in the presence or absence of WT1 or DAX-1. Immunohistochemistry and H-scoring showed that DAX-1 was ubiquitously present in epithelial and stromal cells of both tissues. WT1, on the other hand, was preferentially expressed in stromal (vs. epithelial) cells. Moreover, WT1 levels in endometriotic stromal cells are significantly down-regulated compared with normal endometrial stromal cells. In summary, WT1 or DAX-1 inhibits cAMP-SF-1 pathway-dependent P450arom expression in cultured human endometriotic and endometrial stromal cells. In vivo down-regulation of WT1 in endometriotic stromal cells (vs. normal endometrial stromal cells) may in part be responsible for aberrantly increased P450arom expression and estrogen formation in this pathological tissue.
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In vitro overexpression studies reflected the in vivo effects of these factors on differential P450arom expression.
“Previously, we demonstrated that in vitro overexpression studies reflected the in vivo effects of these factors on differential P450arom expression (16,17,22).”
From Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis (2009) · cites this paper as [17]
The Results (p. 5) show that overexpressed WT1 and DAX-1 inhibit P450arom promoter activity in cultured stromal cells. In vivo measurements (Endometriosis, pp. 7–8) show lower WT1 in endometriotic stroma, consistent with that finding, but no significant difference in DAX-1 levels between the tissues. The paper therefore does not show that the in vitro results reflected in vivo effects of both factors on differential P450arom expression. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCOUP-TF and WT1 bind to and inhibit the P450arom promoter in endometrial stromal cells.
“Conversely, the transcription factors chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and Wilms' tumor-1 (WT1) bind to and inhibit the P450arom promoter in endometrial stromal cells (16,17).”
From Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis (2009) · cites this paper as [17]
The Discussion (p. 8) reports that COUP-TF inhibits aromatase expression in endometrium and competes with SF-1 for binding to the P450arom promoter. The Results (pp. 5–6) show that WT1 inhibits promoter activity in endometrial stromal cells, but do not show that WT1 itself binds the promoter; they instead describe inhibition of activity mediated by SF-1 binding. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe minus KTS splice isoform of WT1 is a more potent transcriptional regulator compared with the plus KTS isoform.
“We used the minus KTS splice isoform of WT1, which is a more potent transcriptional regulator compared with the plus KTS isoform (17).”
From Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis (2009) · cites this paper as [17]
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References 52 · Cited by 70
- Authors
- Gurates, B., Sebastian, S., Yang, S., Zhou, J., Tamura, M., Fang, Z., Suzuki, T., Sasano, H., & Bulun, S. E.
- Affiliations
- Departments of Obstetrics and Gynecology and Molecular Genetics (B.G., S.S., S.Y., J.Z., M.T., Z.F., S.E.B.), University of Illinois at Chicago, Chicago, Illinois 60612
- University of Illinois Chicago (US)
- Tohoku University (JP)
- Corresponding author
- Bulun, Serdar E.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2002-09-01
- Volume
- 87
- Issue
- 9
- Pages
- 4369-4377
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2076358748
- Semantic Scholar
- 3c0572c450162a7dcbf5b694e356b7339609a70b
- Cited by
- 70
- References
- 52
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 2 · 2015: 1 · 2014: 2 · 2013: 4 · 2012: 2
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Illinois at Chicago
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-38691)
- 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 › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- DAX-1, steroidogenic factor 1, aromatase P450, endometriosis, endometrial stromal cells, eutopic endometrium, cAMP signaling, transcriptional regulation, promoter activity, estrogen synthesis, anti-Müllerian hormone, steroidogenesis
- MeSH terms
- Aromatase, Base Sequence, Biopsy, DNA-Binding Proteins, Endometriosis, Endometrium, Epithelial Cells, Female, Humans, Luciferases, Molecular Sequence Data, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Transcription Factors, Gene Expression Regulation, Enzymologic, Mutagenesis, Site-Directed, Stromal Cells, Receptors, Retinoic Acid, 5' Untranslated Regions, WT1 Proteins, Steroidogenic Factor 1, DAX-1 Orphan Nuclear Receptor
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