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Cited by 35Prostate Cancer Treatment and ResearchEstrogen and related hormone effectsSperm and Testicular Function

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Subcellular Localization Modulates Activation Function 1 Domain Phosphorylation in the Androgen Receptor

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Kesler, Cristina T., Gioeli, Daniel, Conaway, Mark R., Weber, Michael J., Paschal, Bryce M.·2007·Molecular Endocrinology
DOI 10.1210/me.2007-0240
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Abstract

Although the steady-state distribution of the androgen receptor (AR) is predominantly nuclear in androgen-treated cells, androgen-bound AR shuttles between the nucleus and the cytoplasm. In the present study we have addressed how nucleocytoplasmic shuttling contributes to the regulation of AR. Nuclear transport signal fusions were used to force AR localization to the nucleus or cytoplasm of prostate cancer cells, and the effect of localization on shuttling, transcription, androgen binding, and phosphorylation was determined. Fusing the simian virus 40 nuclear localization signal or c-Abl nuclear export signal to AR resulted in androgen-independent localization to the nucleus or cytoplasm, respectively. AR forced to the nucleus was transcriptionally active on prostate-specific antigen and mouse mammary tumor virus promoters driving reporter genes. AR forced to the cytoplasm was largely inactive on the prostate-specific antigen promoter, but, surprisingly, AR was active on the mouse mammary tumor virus promoter and on two endogenous genes examined. Thus, highly transient nuclear localization of AR is sufficient to activate transcription. Androgen dissociation rates and the dissociation constant (KD) of AR for androgen were similar whether AR was localized to the cytoplasm or the nucleus, suggesting the ligand-binding cycle of AR is not strictly linked to its compartmentalization. Using phosphosite antibodies, we found that compartmentalization influences the phosphorylation state of AR. We show there is a bias for androgen-dependent phosphorylation of Ser81, Ser256, and Ser308 in the nucleus and androgen-independent phosphorylation of Ser94 in the cytoplasm. We propose that one function of nucleocytoplasmic shuttling is to integrate the signaling environment in the cytoplasm with AR activity in the nucleus.

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Metadata

Authors
Kesler, C. T., Gioeli, D., Conaway, M. R., Weber, M. J., & Paschal, B. M.
Affiliations
  • University of Virginia Health System (US)
  • University of Virginia (US)
Corresponding author
Paschal, Bryce M.
ORCID
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2007-09-01
Volume
21
Issue
9
Pages
2071-2084
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/me.2007-0240
OpenAlex
W2033851432
Cited by
35
References
52
Citations by year
2023: 1 · 2021: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 2 · 2013: 5 · 2012: 6
FWCI
3.16
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Harvard University
  • National Cancer Institute (P01CA104106)
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 › Reproductive Medicine › Sperm and Testicular Function
Keywords
androgen receptor, subcellular localization, nucleocytoplasmic shuttling, phosphorylation, nuclear localization signal, nuclear export signal, transcriptional activation, androgen binding, prostate cancer cells, phosphosites, cytoplasmic compartmentalization
MeSH terms
Amino Acid Sequence, Animals, Chlorocebus aethiops, Molecular Sequence Data, Phosphorylation, Receptors, Androgen, Protein Structure, Tertiary, COS Cells, NIH 3T3 Cells, Cell Line, Tumor, Mice

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