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Cited by 20Sexual Differentiation and DisordersAdrenal Hormones and DisordersGenomics and Chromatin Dynamics

The -104G nucleotide of the human CYP21 gene is important for CYP21 transcription activity and protein interaction

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Chin, K.·1998·Nucleic Acids Research
DOI 10.1093/nar/26.8.1959PMC PMC147502
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Abstract

CYP21 gene encodes the steroid 21-hydroxylase (P450c21) that is involved in steroidogenesis in the adrenal cortex. Mutations occurring on CYP21 which convert it to the neighboring pseudogene, CYP21P, are found in patients with congenital adrenal hyperplasia (CAH), an autosomal recessive disease. We previously reported that the CYP21P pseudogene had lower transcription activity when compared with the active CYP21 gene. The sequences determining the basal transcription activity of the human CYP21 gene are located within the 166 bp region upstream from the transcriptional start site. Within this region, only 4 nucleotides are different between the active CYP21 and the CYP21P pseudogene; they are located at the -117, -104, -101 and -94 positions from the start site of the gene. Here, we report that the CYP21 gene-specific G nucleotide sequence at the -104 position is required for its basal transcription activity driven by the native TATA box of the human CYP21 gene. When this single nucleotide is changed to the CYP21P sequence, the basal transcription activity decreases by approximately 80% in transient transfection assay. In addition, our data from gel retardation assay show that this sequence is also critical for interaction with nuclear proteins from adrenal cells. These results therefore suggest that the single G sequence of the human CYP21 gene is crucial for the expression of its basal transcription activity, and this may be influenced by the interaction with specific nuclear proteins from the adrenal gland.

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  • Sequences responsible for the difference in expression between CYP21A2 and CYP21A1P have been localized to the first 176 nucleotides, although sequences upstream of this region are required for full expression.

    “Sequences responsible for this difference have been localized to the first 176 nucleotides (176) although sequences upstream of this region are required for full expression.”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [176]

    The Introduction and Discussion localize the expression difference between CYP21 and CYP21P to a 166-bp region, supporting the localization but not the cited sentence’s figure of 176 nucleotides. The citation is attached to that localization; our copy does not establish the subsequent assertion that upstream sequences are required for full expression. No page number is available in our copy. (LLM, conf=0.88)

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  • In cultured mouse Y-1 or human H295 adrenocortical cells, the 5' flanking region of human CYP21A2 drives basal expression of reporter constructs at levels 2.5-8 times higher than the corresponding region of CYP21A1P.

    “In cultured mouse Y-1 or human H295 adrenocortical cells, the 5' flanking region of human CYP21A2 drives basal expression of reporter constructs at levels 2.5-8 times higher than the corresponding region of CYP21A1P (176-178).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [176]

    The Results section reports that a CYP21 5′-flanking reporter construct had approximately eightfold higher transcription activity than its CYP21P counterpart in mouse Y1 cells. The Introduction reports lower CYP21P basal activity in both Y1 and human NCI-H295 cells, but our copy does not give a 2.5-fold value for H295 or establish the full stated range. (LLM, conf=0.86)

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  • CYP21A1P transcripts cannot be detected in primary cultures of human adrenocortical cells, whereas CYP21A2 is appropriately expressed under the same conditions.

    “Similarly, CYP21A1P transcripts cannot be detected in primary cultures of human adrenocortical cells, whereas CYP21A2 is appropriately expressed under the same conditions (170,176).”

    From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [176]

    The Introduction (page unavailable) says the active CYP21 gene is expressed in the adrenal gland, but also says CYP21P is expressed there. The Cell cultures and transcriptional activity analysis section (page unavailable) describes mouse Y1 cells, not primary human adrenocortical cultures. The paper therefore does not establish that CYP21A1P transcripts are undetectable while CYP21A2 is expressed under the claimed conditions. (LLM, conf=0.84)

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Research works printed but not linked: 7

  1. White,P.C., Grossberger,D., Onufer,B.J., Chaplin,D.D. New,M.I., Dupont,B. and Strominger, J.L. (1985) Proc. Natl. Acad. Sci. USA, 82, 1089-1093.
  2. Higashi,Y., Yoshioka,H., Yamane,M., Gotoh,O. and Fujii-Kuriyama,Y. (1986) Proc. Natl. Acad. Sci. USA, 83, 2841-2845.
  3. White,P.C., New,M.I. and Dupont,B. (1986) Proc. Natl. Acad. Sci. USA., 83, 5111-5115.
  4. Morel,Y., Bristow,J., Gitelman,S.E. and Miller,W.L. (1990) Proc. Natl. Acad. Sci. USA, 86, 6582-6586.
  5. Gorman,C.M., Merlino,G.T., Willingham,M.C., Pastan,I. and Howard,B.H. (1982) Proc. Natl. Acad. Sci. USA, 79, 6777-6781.
  6. Miskimins,W.K., Roberts,M.P., McClelland,A. and Ruddle,F.H. (1985) Proc. Natl. Acad. Sci. USA., 82, 6741-6744.
  7. Kadonaga,J.T. and Tjian,R. (1986) Proc. Natl. Acad. Sci. USA, 83, 5889-5893.

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Authors
Chin, K.
Affiliations
Taipei Medical University (TW)
Corresponding author
Chin, K.
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
1998-04-15
Volume
26
Issue
8
Pages
1959-1964
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/26.8.1959
PMC
PMC147502
OpenAlex
W2161042919
Cited by
20
References
32
Citations by year
2025: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2017: 1 · 2016: 1 · 2013: 1 · 2012: 1
FWCI
0.35
Type
journal article
Language
en
Open access
Locations
  • Nucleic Acids Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Council
  • National Health Research Institutes
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
CYP21, 21-hydroxylase, P450c21, congenital adrenal hyperplasia, basal transcription, TATA box, transcription start sites, nuclear protein binding, adrenal cortex, steroidogenesis
MeSH terms
Adrenal Cortex, Animals, Base Sequence, Cattle, Cell Nucleus, Cloning, Molecular, Escherichia coli, Guanine, HeLa Cells, Humans, Kinetics, Molecular Sequence Data, Pseudogenes, Recombinant Proteins, Regulatory Sequences, Nucleic Acid, Steroid 21-Hydroxylase, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Mutagenesis, Site-Directed, Point Mutation, Genes, Reporter, Mice

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