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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Self-citation
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Background
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Background
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Role of conserved hydrophobic amino acids in androgen receptor AF-1 function
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“Regions within the N-terminus of the human and rat receptors important for transactivation have been delineated by deletion analysis, the use of fusion proteins and point mutations (Jenster et al. 1991, 1995, Simental et al. 1991, Chamberlain et al. 1996).”
Method
Retinoic Acid Receptor-α Is Stabilized in a Repressive State by Its C-Terminal, Isotype-Specific F Domain
Farboud, B., & Privalsky, M. L. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0236 · Cited by 33
Androgen stimulated cellular proliferation in the human prostate cancer cell line LNCaP is associated with reduced retinoblastoma protein expression
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“[Jenster et al., 1991, 1993; Kemppainen et al., 1992; Chang et al., 1995].”
Background
A Novel Mutation in the CAG Triplet Region of Exon 1 of Androgen Receptor Gene Causes Complete Androgen Insensitivity Syndrome in a Large Kindred1
Zhu, Y., Cai, L., Cordero, J. J., Canovatchel, W. J., Katz, M. D., & Imperato‐McGinley, J. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.5.5695 · Cited by 33
“Between the DNA-binding domain and the steroid-binding domain is the hinge region, which is encoded by the 59 portion of exon 4 and which contains the nuclear translocation signal ( 7 , 8).”
Background
Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor–Chromatin Interactions
Dalal, K., Che, M., Que, N. S., Sharma, A., Yang, R., Lallous, N., Borgmann, H., Özistanbullu, D., Tse, R., Ban, F., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0259 · Cited by 33
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Trinucleotide repeat disease
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Identification of a Novel Phosphorylation Site in Human Androgen Receptor by Mass Spectrometry
Zhu, Z., Becklin, R. R., Desiderio, D. M., & Dalton, J. T. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5030 · Cited by 32
Physiology and pathophysiology of androgen action
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Tetrahydrogestrinone Is an Androgenic Steroid that Stimulates Androgen Receptor-Mediated, Myogenic Differentiation in C3H10T1/2 Multipotent Mesenchymal Cells and Promotes Muscle Accretion in Orchidectomized Male Rats
Jasuja, R., Catlin, D. H., Miller, A., Chang, Y., Herbst, K. L., Starcevic, B., Artaza, J. N., Singh, R., Datta, G. D., Sarkissian, A., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0448 · Cited by 31
Role of androgen receptor splice variants, their clinical relevance and treatment options
Wach, S., Taubert, H. W., & Cronauer, M. V. (2019) · World Journal of Urology · doi:10.1007/s00345-018-02619-0 · Cited by 30
Steroid Hormone Receptors: Activators of Gene Transcription
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Self-citation
Modulation of Nuclear Receptor Function by Chromatin Modifying Factor TIP60
Jaiswal, B., & Gupta, A. K. (2018) · Endocrinology · doi:10.1210/en.2017-03190 · Cited by 32
“tinct structural and functional domains (138, 139).”
Human androgen receptor expressed in HeLa cells activates transcriptionin vitro
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Androgen signal transduction and prostatic carcinoma
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“binding domain of the ligand-free AR appears to function as a repessor preventing constitutive activation in the absence of androgen [15].”
Background
A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility*
Giwercman, Y. L., Nikoshkov, A., Byström, B., Pousette, Å., Arver, S., & Wedell, A. (2001) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2001.01308.x · Cited by 29
Presence of Androgen Receptor Variant in Neuronal Lipid Rafts
Garza-Contreras, J., Duong, P., Snyder, B., Schreihofer, D. A., & Cunningham, R. L. (2017) · eNeuro · doi:10.1523/eneuro.0109-17.2017 · Cited by 28
“The classic AR has four distinct regions: a regulatory NH2 terminal domain (NTD; Ferro et al., 2002; Ding et al., 2004, 2005; Callewaert et al., 2006; Claessens et al., 2008), a DNA binding domain (DBD), a hinge domain, and a ligand binding domain (LBD) extending to the C-terminal domain (CTD; Claessens et al., 2008).”
BackgroundInfluential
Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies
Obst, J. K., Wang, J., Jian, K., Williams, D. E., Tien, A. H., Mawji, N. R., Tam, T. W., Yang, Y. C., Andersen, R. J., Chi, K. N., et al. (2019) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.9b00065 · Cited by 29
Evolution of the androgen receptor: Perspectives from human health to dancing birds
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Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells
Streicher, W., Luedeke, M., Azoitei, A., Zengerling, F., Herweg, A., Genze, F., Schrader, M. G., Schrader, A. J., & Cronauer, M. V. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098566 · Cited by 28
“deletion of the AR-LBD situated in the C-terminus of the AR, results in constitutive activation of the receptor molecule [35].”
Background
Androgens and androgen receptor in prostate and ovarian malignancies
Sadar, M. D. (2003) · Frontiers in bioscience · doi:10.2741/1063 · Cited by 26
“The AR is unique from other nuclear receptors in the way that AF1 contributes most, if not all, of the activity to the ligand-bound AR rather than AF-2 (67, 68, 89, 90).”
BackgroundInfluential
Androgen receptor with short polyglutamine tract preferably enhances Wnt/β-catenin-mediated prostatic tumorigenesis
He, Y., Mi, J., Olson, A. W., Aldahl, J., Hooker, E., Yu, E., Le, V. L., Lee, D., Kim, W. K., Robins, D. M., et al. (2020) · Oncogene · doi:10.1038/s41388-020-1214-7 · Cited by 25
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“The amino-terminal of the AR, or N-terminal domain (NTD), is both necessary and sufficient for AR-mediated transcription [8].”
Background
Targeting the N-terminal domain of the androgen receptor: The effective approach in therapy of CRPC
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Calmodulin protects androgen receptor from calpain-mediated breakdown in prostate cancer cells
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Background
A novel splice site mutation in the androgen receptor gene results in exon skipping and a non-functional truncated protein
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Background
Improved androgen specificity of AR-EcoScreen by CRISPR based glucocorticoid receptor knockout
Zwart, N., Andringa, D., de Leeuw, W.-J., Kojima, H., Iida, M., Houtman, C. J., de Boer, J., Kool, J., Lamoree, M. H., & Hamers, T. (2017) · Toxicology in Vitro · doi:10.1016/j.tiv.2017.08.004 · Cited by 23
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Background
Tracing the Evolution of Sex Hormones and Receptor‐Mediated Immune Microenvironmental Differences in Prostate and Bladder Cancers: From Embryonic Development to Disease
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“functional studies showed that deletion of the AR-ligandbinding domain results in the constitutive activation of the AR [17].”
Background

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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