Cited by 525Prostate Cancer Treatment and ResearchEstrogen and related hormone effectsHormonal and reproductive studies

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Domains of the Human Androgen Receptor Involved in Steroid Binding, Transcriptional Activation, and Subcellular Localization

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Jenster, Guido, van der Korput, Hetty A. G. M., van Vroonhoven, Cor, van der Kwast, Theo H., Trapman, Jan, Brinkmann, Albert O.·1991·Molecular Endocrinology

DOI 10.1210/mend-5-10-1396

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Abstract

A series of human androgen receptor (AR) deletion mutants was constructed to study the relationship between the structural domains and their different functions in the AR protein. Human AR mutants were expressed in COS-1 and HeLa cells to investigate hormone binding, transcriptional activation, and subcellular localization. The wild-type human AR (AR 1–910) was expressed as a 110- to 112-kDa doublet, as revealed on immunoblots. All mutant AR proteins also migrated as doublets, except for one. This AR has a deletion from amino acid residues 51–211 and migrated as a single protein band, possibly due to altered posttranslational modification. The AR steroid-binding domain is encoded by approximately 250 amino acid residues in the Cterminal end. Deletions in this domain as well as truncation of the last 12 C-terminal amino acid residues abolished hormone binding. Cotransfection studies in HeLa cells showed that transcriptional activation of an androgen-regulated reporter gene construct was induced by the wildtype human AR. Mutational analysis revealed two regions in the N-terminal part, encoded by amino acid residues 51–211 and 244–360, to be essential for this transcriptional activation. Deletion of the hormone-binding domain yielded a constitutively active AR protein, indicating that in the absence of hormone this domain displays an inhibitory function. In the presence of its ligand, the wild-type AR was located in the cell nucleus. In the absence of androgens the receptor was mainly nuclear, but cytoplasmic localization was observed as well. In contrast, an AR deletion mutant lacking part of the DNAbinding domain and part of the hinge region was exclusively cytoplasmic in the absence of hormone. This mutant AR lacks a region that is highly conserved among steroid receptors and homologous to the simian virus-40 large T-antigen- and nucleoplas-min-nuclear localization signals. Transformation by hormone directed this mutant to the nucleus, indicating the presence of a second, hormone-dependent nuclear targeting mechanism.

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Cyclin D3/CDK11p58 Complex Is Involved in the Repression of Androgen Receptor
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“The transcriptional activation unit 1 (TAU1) and TAU5 motifs in the AR N-terminal domain (NTD) (residues 101 to 370 and 360 to 485, respectively) as well as the AF-2 motif in the AR LBD have been implicated in directly contacting p160 proteins and mediating transcription (1, 23, 31, 48).”
Background
The Presence of Both the Amino- and Carboxyl-Terminal Domains in the AR Is Essential for the Completion of a Transcriptionally Active Form with Coactivators and Intranuclear Compartmentalization Common to the Steroid Hormone Receptors: A Three-Dimensional Imaging Study
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“Similar to other nuclear receptors, the AR is organized into three distinct domains: An N-terminal domain (NTD), followed by a DNA binding (DBD) and a C-terminal ligand binding domain (LBD) [4,5].”
Background
Differential Effect of Small Ubiquitin-Like Modifier (SUMO)-ylation of the Androgen Receptor in the Control of Cooperativity on SelectiveVersusCanonical Response Elements
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“Besides transcriptional activation region, the NTD also includes homopolymeric amino acid regions (polyglutamine and polyglycine repeats) that function in transcriptional regulation in interaction with other receptor regions, and in determining the three-dimensional structure of the receptor (Evans, 1988; Jenster et a…”
BackgroundInfluential
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Cyclin D1 Binding to the Androgen Receptor (AR) NH2-Terminal Domain Inhibits Activation Function 2 Association and Reveals Dual Roles for AR Corepression
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Structural Characterization of the Human Androgen Receptor Ligand-binding Domain Complexed with EM5744, a Rationally Designed Steroidal Ligand Bearing a Bulky Chain Directed toward Helix 12
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Reduction of Coactivator Expression by Antisense Oligodeoxynucleotides Inhibits ER Transcriptional Activity and MCF-7 Proliferation
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“Like other members of the steroid receptor family the gene comprises three functional domains: parts of the N terminal end promote the transactivation of certain target genes; a DNA binding domain facilitates binding of the androgen receptor protein onto promoter regions of specific target genes; and a steroid binding…”
Background
Beyond the Ligand-Binding Pocket: Targeting Alternate Sites in Nuclear Receptors
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Self-citation
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Background
Androgen receptor polymorphism (CAG repeats) and androgenicity
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“Although the LBD is responsible for binding to androgen and some co-factors, it may also serve as a negative regulator of AR transcription activity based on several observations that deletion of LBD generates androgen-independent constitutively active AR mutants [18-20].”
Background
Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain
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A point mutation in the second zinc finger of the DNA-binding domain of the androgen receptor gene causes complete androgen insensitivity in two siblings with receptor-positive androgen resistance
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Background
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Self-citation
Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor
Singam, E. R. A., Tachachartvanich, P., Merrill, M. A. L., Smith, M. T., & Durkin, K. A. (2019) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.9b05654 · Cited by 54

Authors: Jenster, G., van der Korput, H. A. G. M., van Vroonhoven, C., van der Kwast, T. H., Trapman, J., & Brinkmann, A. O.
Affiliations: Erasmus University Rotterdam (NL)
ORCID: Jenster, Guido
Venue: Molecular Endocrinology
Publisher: The Endocrine Society
Published: 1991-10
Volume: 5
Issue: 10
Pages: 1396-1404
ISSN: 0888-8809 (ISSN-L)
1944-9917
DOI: 10.1210/mend-5-10-1396
OpenAlex: W2002791165
Cited by: 523
References: 52
Citations by year: 2026: 6 · 2025: 9 · 2024: 13 · 2023: 4 · 2022: 8 · 2021: 9 · 2020: 12 · 2019: 11 · 2018: 15 · 2017: 16 · 2016: 18 · 2015: 12 · 2014: 14 · 2013: 17 · 2012: 18
FWCI: 25.65
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Molecular Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords: androgen receptor, steroid-binding domain, transcriptional activation, subcellular localization, nuclear localization signal, nuclear targeting, hormone binding, constitutively active receptor, deletion mutants, DNA-binding domain, hinge region, post-translational modification
MeSH terms: Animals, Binding Sites, Cell Line, Chromosome Deletion, DNA-Binding Proteins, Genetic Vectors, HeLa Cells, Humans, Immunohistochemistry, Plasmids, Receptors, Androgen, Recombinant Proteins, Transcription, Genetic, Transfection, Restriction Mapping, Chloramphenicol O-Acetyltransferase, Metribolone

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Domains of the Human Androgen Receptor Involved in Steroid Binding, Transcriptional Activation, and Subcellular Localization

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