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GATA-4 and GATA-6 Modulate Tissue-Specific Transcription of the Human Gene for P450c17 by Direct Interaction with Sp1
Open accessAbstract
Cytochrome P450c17 catalyzes steroidogenic 17α-hydroxylase and 17,20 lyase activities. Expression of the gene for P450c17 is cAMP dependent, tissue specific, developmentally programmed, and varies among species. Binding of Sp1, Sp3, and NF1-C (nuclear factor 1-C) to the first 227 bp of 5′flanking DNA (−227/LUC) is crucial for basal transcription in human NCI-H295A adrenal cells. Human placental JEG-3 cells contain Sp1, Sp3, and NF1, but do not express −227/LUC, even when transfected with a vector expressing steroidogenic factor 1 (SF-1). Therefore, other factors are essential for basal expression of P450c17. Deoxyribonuclease I footprinting and EMSAs identified a GATA consensus site at −64/−58 and an SF-1 site at −58/−50. RT-PCR identified GATA-4, GATA-6, and SF-1 in NCI-H295A cells and GATA-2 and GATA-3, but not GATA-4, GATA-6, or SF-1 in JEG-3 cells. Cotransfection of either GATA-4 or GATA-6 without SF-1 activated −227/LUC in JEG-3 cells, but cotransfection of GATA-2 or GATA-3 with or without SF-1 did not. Surprisingly, mutation of the GATA binding site in −227/LUC increased GATA-4 or GATA-6 induced activity, whereas mutation of the Sp1/Sp3 site decreased it. Furthermore, promoter constructs including the GATA site, but excluding the Sp1/Sp3 site at −196/−188, were not activated by GATA-4 or GATA-6, suggesting an interaction between Sp1/Sp3 and GATA-4 or GATA-6. Glutathione-S-transferase pull-down experiments and coimmunoprecipitation demonstrated interaction between GATA-4 or GATA-6 and Sp1, but not Sp3. Chromatin immunoprecipitation assays confirmed that this GATA-4/6 interaction with Sp1 occurred at the Sp site in the P450c17 promoter in NCI-H295A cells. Demethylation with 5-aza-2-deoxycytidine permitted JEG-3 cells to express endogenous P450c17, SF-1, GATA-4, GATA-6, and transfected −227/LUC. Thus, GATA-4 or GATA-6 and Sp1 together regulate expression of P450c17 in adrenal NCI-H295A cells and methylation of P450c17, GATA-4 and GATA-6 silence the expression of P450c17 in placental JEG-3 cells.
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“Adrenal expression of human CYP17A1 requires the transcription factors SF1, SP1, SP3, CTF2, CTF5, GATA4 and GATA6 (250 -255).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [254]
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Metadata
- Authors
- Flück, C. E., & Miller, W. L.
- Affiliations
- Department of Pediatrics and The Metabolic Research Unit, University of California San Francisco, San Francisco, California 94143-0978
- University of California, San Francisco (US)
- Corresponding author
- Miller, Walter L.
- ORCID
- Miller, Walter L.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-05-01
- Volume
- 18
- Issue
- 5
- Pages
- 1144-1157
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2147982925
- Semantic Scholar
- 6bff6834baa403e050cbc7e2c59f353b777e6e28
- Cited by
- 127
- References
- 71
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 2 · 2013: 8 · 2012: 6
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Funders
- North Carolina State University
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- National Cancer Institute
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-41958, R01HD041958)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- CYP17, GATA4, GATA6, Sp1, transcription factor interaction, steroidogenic factor 1, steroidogenesis, 5'-flanking region, tissue-specific gene expression, adrenal cells, placenta, transcriptional regulation, GATA binding sites
- MeSH terms
- Animals, Binding Sites, Cells, Cultured, Cytochrome P-450 Enzyme System, DNA-Binding Proteins, Drosophila, Female, Gene Expression Regulation, Humans, Methylation, Placenta, Promoter Regions, Genetic, Transcription Factors, Transcriptional Activation, Sp1 Transcription Factor, Neurofibromin 1, GATA4 Transcription Factor, GATA6 Transcription Factor, Steroidogenic Factor 1
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