The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells

Javid A. Dar, Khalid Z. Masoodi, Kurtis Eisermann, Sudhir Isharwal, Junkui Ai, Laura E. Pascal, Joel B. Nelson, Zhou Wang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Androgen-independent nuclear localization is required for androgen receptor (AR) transactivation in castration-resistant prostate cancer (CRPC) and should be a key step leading to castration resistance. However, mechanism(s) leading to androgen-independent AR nuclear localization are poorly understood. Since the N-terminal domain (NTD) of AR plays a role in transactivation under androgen-depleted conditions, we investigated the role of the NTD in AR nuclear localization in CRPC. Deletion mutagenesis was used to identify amino acid sequences in the NTD essential for its androgen-independent nuclear localization in C4-2, a widely used CRPC cell line. Deletion mutants of AR tagged with green fluorescent protein (GFP) at the 5′-end were generated and their signal distribution was investigated in C4-2 cells by fluorescent microscopy. Our results showed that the region of a.a. 294-556 was required for androgen-independent AR nuclear localization whereas a.a. 1-293 mediates Hsp90 regulation of AR nuclear localization in CRPC cells. Although the region of a.a. 294-556 does not contain a nuclear import signal, it was able to enhance DHT-induced import of the ligand binding domain (LBD). Also, transactivation of the NTD could be uncoupled from its modulation of AR nuclear localization in C4-2 cells. These observations suggest an important role of the NTD in AR intracellular trafficking and androgen-independent AR nuclear localization in CRPC cells.

Original languageEnglish (US)
Pages (from-to)473-480
Number of pages8
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume143
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Castration
Androgen Receptors
Prostatic Neoplasms
Cells
Androgens
Transcriptional Activation
Mutagenesis
Cell Nucleus Active Transport
Green Fluorescent Proteins
Microscopy
Amino Acid Sequence
Microscopic examination
Modulation
Ligands
Amino Acids
Cell Line

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Cite this

The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells. / Dar, Javid A.; Masoodi, Khalid Z.; Eisermann, Kurtis; Isharwal, Sudhir; Ai, Junkui; Pascal, Laura E.; Nelson, Joel B.; Wang, Zhou.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 143, 01.01.2014, p. 473-480.

Research output: Contribution to journalArticle

Dar, Javid A. ; Masoodi, Khalid Z. ; Eisermann, Kurtis ; Isharwal, Sudhir ; Ai, Junkui ; Pascal, Laura E. ; Nelson, Joel B. ; Wang, Zhou. / The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells. In: Journal of Steroid Biochemistry and Molecular Biology. 2014 ; Vol. 143. pp. 473-480.
@article{2eb67bf468de43caaf4593e29571595d,
title = "The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells",
abstract = "Androgen-independent nuclear localization is required for androgen receptor (AR) transactivation in castration-resistant prostate cancer (CRPC) and should be a key step leading to castration resistance. However, mechanism(s) leading to androgen-independent AR nuclear localization are poorly understood. Since the N-terminal domain (NTD) of AR plays a role in transactivation under androgen-depleted conditions, we investigated the role of the NTD in AR nuclear localization in CRPC. Deletion mutagenesis was used to identify amino acid sequences in the NTD essential for its androgen-independent nuclear localization in C4-2, a widely used CRPC cell line. Deletion mutants of AR tagged with green fluorescent protein (GFP) at the 5′-end were generated and their signal distribution was investigated in C4-2 cells by fluorescent microscopy. Our results showed that the region of a.a. 294-556 was required for androgen-independent AR nuclear localization whereas a.a. 1-293 mediates Hsp90 regulation of AR nuclear localization in CRPC cells. Although the region of a.a. 294-556 does not contain a nuclear import signal, it was able to enhance DHT-induced import of the ligand binding domain (LBD). Also, transactivation of the NTD could be uncoupled from its modulation of AR nuclear localization in C4-2 cells. These observations suggest an important role of the NTD in AR intracellular trafficking and androgen-independent AR nuclear localization in CRPC cells.",
author = "Dar, {Javid A.} and Masoodi, {Khalid Z.} and Kurtis Eisermann and Sudhir Isharwal and Junkui Ai and Pascal, {Laura E.} and Nelson, {Joel B.} and Zhou Wang",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.jsbmb.2014.03.004",
language = "English (US)",
volume = "143",
pages = "473--480",
journal = "Journal of Steroid Biochemistry and Molecular Biology",
issn = "0960-0760",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - The N-terminal domain of the androgen receptor drives its nuclear localization in castration-resistant prostate cancer cells

AU - Dar, Javid A.

AU - Masoodi, Khalid Z.

AU - Eisermann, Kurtis

AU - Isharwal, Sudhir

AU - Ai, Junkui

AU - Pascal, Laura E.

AU - Nelson, Joel B.

AU - Wang, Zhou

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Androgen-independent nuclear localization is required for androgen receptor (AR) transactivation in castration-resistant prostate cancer (CRPC) and should be a key step leading to castration resistance. However, mechanism(s) leading to androgen-independent AR nuclear localization are poorly understood. Since the N-terminal domain (NTD) of AR plays a role in transactivation under androgen-depleted conditions, we investigated the role of the NTD in AR nuclear localization in CRPC. Deletion mutagenesis was used to identify amino acid sequences in the NTD essential for its androgen-independent nuclear localization in C4-2, a widely used CRPC cell line. Deletion mutants of AR tagged with green fluorescent protein (GFP) at the 5′-end were generated and their signal distribution was investigated in C4-2 cells by fluorescent microscopy. Our results showed that the region of a.a. 294-556 was required for androgen-independent AR nuclear localization whereas a.a. 1-293 mediates Hsp90 regulation of AR nuclear localization in CRPC cells. Although the region of a.a. 294-556 does not contain a nuclear import signal, it was able to enhance DHT-induced import of the ligand binding domain (LBD). Also, transactivation of the NTD could be uncoupled from its modulation of AR nuclear localization in C4-2 cells. These observations suggest an important role of the NTD in AR intracellular trafficking and androgen-independent AR nuclear localization in CRPC cells.

AB - Androgen-independent nuclear localization is required for androgen receptor (AR) transactivation in castration-resistant prostate cancer (CRPC) and should be a key step leading to castration resistance. However, mechanism(s) leading to androgen-independent AR nuclear localization are poorly understood. Since the N-terminal domain (NTD) of AR plays a role in transactivation under androgen-depleted conditions, we investigated the role of the NTD in AR nuclear localization in CRPC. Deletion mutagenesis was used to identify amino acid sequences in the NTD essential for its androgen-independent nuclear localization in C4-2, a widely used CRPC cell line. Deletion mutants of AR tagged with green fluorescent protein (GFP) at the 5′-end were generated and their signal distribution was investigated in C4-2 cells by fluorescent microscopy. Our results showed that the region of a.a. 294-556 was required for androgen-independent AR nuclear localization whereas a.a. 1-293 mediates Hsp90 regulation of AR nuclear localization in CRPC cells. Although the region of a.a. 294-556 does not contain a nuclear import signal, it was able to enhance DHT-induced import of the ligand binding domain (LBD). Also, transactivation of the NTD could be uncoupled from its modulation of AR nuclear localization in C4-2 cells. These observations suggest an important role of the NTD in AR intracellular trafficking and androgen-independent AR nuclear localization in CRPC cells.

UR - http://www.scopus.com/inward/record.url?scp=84905712572&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905712572&partnerID=8YFLogxK

U2 - 10.1016/j.jsbmb.2014.03.004

DO - 10.1016/j.jsbmb.2014.03.004

M3 - Article

C2 - 24662325

AN - SCOPUS:84905712572

VL - 143

SP - 473

EP - 480

JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

ER -