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Cited by 127Estrogen and related hormone effectsGenomics and Chromatin DynamicsAdrenal Hormones and Disorders

GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by direct interaction with Sp1

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Flück, Christa E., Miller, Walter L.·2004·Molecular Endocrinology
DOI 10.1210/me.2003-0342
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Abstract

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.

    “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]

    The opening passage (p. 1) links SF-1, Sp1/Sp3, and the NF1-C variants CTF2 and CTF5 to regulation of the human P450c17 promoter in adrenal cells. But the paper says GATA-4 or GATA-6 can regulate expression, not that both are required; the Discussion (p. 10) also says GATA-4 is minimal or absent in the adult adrenal. The claim overstates the evidence by presenting every listed factor as individually required for adrenal expression. (LLM, conf=0.90)

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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
DOI
10.1210/me.2003-0342
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
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 › Genetics › 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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