Characterization of nuclear import of the domain-specific androgen receptor in association with the importin α/β and Ran-guanosine 5′-triphosphate systems.

Kaku, Natsuko; Matsuda, Ken-ichi; Tsujimura, Atsushi; Kawata, Mitsuhiro

doi:10.1210/en.2008-0137

Cited by 58Nuclear Structure and FunctionProstate Cancer Treatment and ResearchEstrogen and related hormone effects

Characterization of nuclear import of the domain-specific androgen receptor in association with the importin α/β and Ran-guanosine 5′-triphosphate systems.

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Kaku, Natsuko, Matsuda, Ken-ichi, Tsujimura, Atsushi, Kawata, Mitsuhiro·2008·Endocrinology

DOI 10.1210/en.2008-0137PMC PMC2488236

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Abstract

Androgen induces androgen receptor (AR) nuclear import, which allows AR to act as a transcriptional factor and ultimately leads to biological activity. However, the mechanism of AR translocation to the nucleus is still unclear. In the present study, we assessed the nuclear import abilities of each domain of AR and their mechanisms related to Ran and importin alpha/beta using green fluorescent protein real-time imaging. The localization of AR to the nucleus in the absence and presence of ligands was dependent upon a complex interplay of the amino terminal transactivation domain (NTD), the DNA binding domain (DBD), and the ligand binding domain (LBD). NTD and DBD showed ligand-independent nuclear import ability, whereas LBD had ligand-dependent transport. In addition, AR deletion mutant lacking DBD was distributed in the cytoplasm regardless of ligand existence, suggesting that the remaining domains, NTD and LBD, are responsible for AR cytoplasmic localization. Cotransfection with a dominant negative form of Ran dramatically inhibited the nuclear import of all AR domains, and a dominant negative form of importin alpha prevented AR and DBD import. Importin beta-knockdown strongly blocked DBD import. These results indicate that there are two additional nuclear localization signals (NLSs) in the NTD and LBD, and there are distinct pathways used to attain domain-specific AR nuclear import: the NLS of DBD is Ran and importin alpha/beta-dependent, whereas the NLSs of NTD and LBD are Ran dependent but importin alpha/beta-independent. Our data suggest that the nuclear import of AR is regulated by the interplay between each domain of the AR.

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Movement of the androgen receptor into the nucleus is largely dependent upon the nuclear localization signal present in the hinge region of the receptor, with a portion of that regulation also found within the N-terminal domain.
“The movement of the AR into the nucleus is largely dependent upon the nuclear localization signal (NLS) present in the hinge region of the receptor; however, a portion of that regulation is also found within the NTD.”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [70]
Two additional nuclear localization signals exist in the N-terminal domain and ligand-binding domain with distinct import pathways: the DBD NLS is Ran and importin alpha/beta dependent, whereas the NTD and LBD NLS are Ran dependent but importin alpha/beta independent.
“Two additional NLS exist in the NTD in LBD with distinct pathways for import: the NLS of the DBD is Ran and importin ␣/␤ dependent, whereas the NLS of the NTD and LBD are Ran dependent but importin ␣/␤ independent (70).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [70]
The N-terminal domain and DNA-binding domain have ligand-independent nuclear import ability, whereas the ligand-binding domain exhibits ligand-dependent activity.
“The NTD and DNA-binding domain (DBD) have ligand-independent nuclear import ability, whereas the LBD exhibits ligand-dependent activity (70).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [70]

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Authors: Kaku, N., Matsuda, K.-I., Tsujimura, A., & Kawata, M.
Affiliations: Kyoto Prefectural University of Medicine (JP)
Corresponding author: Kawata, Mitsuhiro
ORCID: Kaku, Natsuko
Matsuda, Ken-ichi
Kawata, Mitsuhiro
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2008-04-17
Volume: 149
Issue: 8
Pages: 3960-3969
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2008-0137
PMC: PMC2488236
OpenAlex: W2049866636
Cited by: 58
References: 42
Citations by year: 2025: 2 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 5
FWCI: 1.92
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Endocrinology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords: androgen receptor, nuclear import, nuclear localization signal, importin alpha, importin beta, Ran GTPase, ligand-binding domain, DNA-binding domain, nuclear transport, androgen signaling
MeSH terms: Animals, Cell Nucleus, Chlorocebus aethiops, Cloning, Molecular, Humans, Protein Binding, Receptors, Androgen, Recombinant Proteins, Substrate Specificity, Tissue Distribution, Transfection, Protein Structure, Tertiary, COS Cells, Nuclear Localization Signals, ran GTP-Binding Protein, Active Transport, Cell Nucleus, alpha Karyopherins, beta Karyopherins

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Characterization of nuclear import of the domain-specific androgen receptor in association with the importin α/β and Ran-guanosine 5′-triphosphate systems.

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