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Cited by 202Hormonal Regulation and HypertensionRenin-Angiotensin System StudiesEstrogen and related hormone effects

Angiotensin II and Potassium Regulate Human CYP11B2 Transcription through Common cis-Elements

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Clyne, Colin D., Zhang, Yin, Slutsker, Liliya, Mathis, J. Michael, White, Perrin C., Rainey, William E.·1997·Molecular Endocrinology
DOI 10.1210/mend.11.5.9920
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Abstract

Aldosterone synthase is a mitochondrial enzyme that catalyzes the conversion of 11-deoxycorticosterone to the potent mineralocorticoid aldosterone. The gene encoding aldosterone synthase, CYP11B2, is expressed in the zona glomerulosa of the adrenal cortex. Although the major physiological regulators of aldosterone production are angiotensin II (ANG II) and potassium (K+), the mechanisms by which these compounds regulate CYP11B2 transcription are unknown. Therefore we analyzed the human CYP11B2 5′-flanking region using a transient transfection expression system in the H295R human adrenocortical cell line. ANG II and K+ increased expression of a luciferase reporter construct containing 2015 bp of human CYP11B2 5′-flanking DNA. This response was mimicked by treatment with the calcium channel activator BAYK8644, whereas activation of the protein kinase C pathway with 12-o-tetradecanoylphorbol-13-acetate had no effect. Reporter gene activity was also increased after activation of cAMP-dependent pathways by (Bu)2cAMP. Deletion, mutation, and deoxyribonuclease I footprinting analyses of the CYP11B2 5′-flanking region identified two distinct elements at positions −71/−64 (TGACGTGA) and −129/−114 (CTCCAGCCTTGACCTT) that were both required for full basal reporter gene activity and for maximal induction by either cAMP or calcium-signaling pathways. The −71/−64 element, which resembles a consensus cAMP response element (CRE), bound CRE-binding proteins from H295R cell nuclear extracts as determined by electrophoretic mobility shift analysis. Analysis of the −129/−114 element using electrophoretic mobility shift analysis demonstrated binding of the orphan nuclear receptors steroidogenic factor 1 and chicken ovalbumin upstream promoter transcription factor. These data demonstrate that ANG II, K+, and cAMP-signaling pathways utilize the same SF-1 and CRE-like cis-elements to regulate human CYP11B2 expression.

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  • Transcription of the CYP11B2 gene encoding P450c11AS is induced by potassium and angiotensin II activation of the protein kinase C pathway, and requires the transcription factors SF1, NURR1 and NGFIB and possibly other factors.

    “Transcription of the CYP11B2 gene encoding P450c11AS is induced by potassium and angiotensin II activation of the protein kinase C pathway (460), and requires the transcription factors SF1, NURR1 and NGFIB (461) and possibly other factors (462).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [460]

    Citation 460 is attached to the claim that potassium and angiotensin II induce CYP11B2 transcription through protein kinase C. In “Signaling Pathways Regulating CYP11B2,” the paper says calcium signaling increases transcription but protein kinase C does not appear to regulate it; the Abstract likewise reports no effect from protein kinase C activation. The separately cited transcription-factor claim is not part of this verdict. (LLM, conf=0.92)

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  • CYP11B2 transcription in granulosa cells is induced by potassium and by angiotensin-II, in both cases stimulating calcium influx and stimulation of PKC and CAMKK signaling.

    “CYP11B2 transcription in granulosa cells is induced by potassium and by angiotensin-II, in both cases stimulating calcium (Ca2+) influx and stimulation of PKC and calmodulin-dependent protein kinase kinase (CAMKK) intracellular signaling (75, 76).”

    From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [75]

    The paper reports that angiotensin II and potassium induce CYP11B2 reporter expression through calcium-dependent signaling in adrenal glomerulosa cells and the H295R adrenocortical cell line, not granulosa cells (Introduction; Signaling Pathways Regulating CYP11B2). It explicitly says PKC does not appear to regulate this transcription, and it identifies CaMK as a possible link rather than establishing CAMKK signaling (Multiple Signaling Pathways; Elements Required for CYP11B2 Expression). (LLM, conf=0.90)

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1 retracted

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Research works printed but not linked: 2

  1. [4]4. Quinn SJ, Williams GH 1992 Regulation of aldosterone secretion. In: James VHT (ed) The Adrenal Gland. Raven Press, New York, pp 159-189
  2. [15]15. Kawamoto T, Mitsuuchi Y, Toda K, Yokoyama Y, Miyahara K, Miura S, Ohnishi T, Ichikawa Y, Nakao K, Imura H, Ulick S, Shizuta,Y 1992 Role of steroid 11␤- hydroxylase and steroid 18-hydroxylase in the biosyn- thesis of glucocorticoids and mineralocorticoids in hu- mans. Proc Natl Acad Sci USA 89:1458-1462

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Authors
Clyne, C. D., Zhang, Y., Slutsker, L., Mathis, J. M., White, P. C., & Rainey, W. E.
Affiliations
  • Department of Obstetrics & Gynecology (C.D.C., Y.Z., J.M.M., W.E.R.), Texas 75235-9032
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Rainey, William E.
ORCID
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
1997-05-01
Volume
11
Issue
5
Pages
638-649
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/mend.11.5.9920
OpenAlex
W1984828684
Semantic Scholar
3ea0519a3ea1cde39187bba8050722e5f438d4d5
Cited by
202
References
53
Citations by year
2026: 4 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 7 · 2017: 3 · 2016: 7 · 2015: 5 · 2014: 7 · 2013: 9 · 2012: 3
FWCI
6.88
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5r01dk042169-12)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-37867, DK42169, DK 43140)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
angiotensin II, potassium, CYP11B2, aldosterone synthase, aldosterone biosynthesis, transcriptional regulation, 5'-flanking region, cis-regulatory elements, cAMP response element, steroidogenic factor 1, SF-1, CRE-binding protein, calcium signaling, protein kinase C, zona glomerulosa, adrenal cortex
MeSH terms
Adrenal Cortex, Angiotensin II, Cell Line, Humans, Potassium, Transcription, Genetic, Transfection, Gene Expression Regulation, Enzymologic, Cytochrome P-450 CYP11B2

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