Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion-independent prostate cancer cells.
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Abstract
Systemic prostate cancer therapy requires androgen ablation, which inhibits the production or action of androgens. Prostate cancer ultimately relapses during androgen ablation, and an androgen depletion-independent (ADI) phenotype emerges. Aberrant androgen receptor (AR) activation underlies therapy resistance at this stage of the disease, and mounting evidence implicates the large and highly disordered AR NH2-terminal domain (NTD) as a key mediator of this activity. In this study, we investigated the role of the NTD transactivation unit 5 (TAU5) domain in mediating AR transcriptional activity in cell-based models of prostate cancer progression. AR replacement and Gal4-based promoter tethering experiments revealed that AR TAU5 had a dichotomous function, inhibiting ligand-dependent AR activity in androgen-dependent prostate cancer cells, while enhancing ligand-independent AR activity in ADI prostate cancer cells. Molecular dissection of TAU5 showed that a WxxLF motif was fully responsible for its ligand-independent activity. Mechanistically, WxxLF did not rely on an interaction with the AR ligand-binding domain to mediate ligand-independent AR activity. Rather, WxxLF functioned as an autonomous transactivation domain. These data show that ligand-dependent and ligand-independent AR activation rely on fundamentally distinct mechanisms, and define WxxLF as the major transactivation motif within the AR TAU5 domain.
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The WxxLF domain is not necessary for conferring ligand-independent activity of the androgen receptor.
“However, this domain is not necessary for conferring ligand-independent activity (67).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [67]
Approximately half of the ligand-independent transcriptional activity of the androgen receptor in castration-recurrent prostate cancer cells is conferred by the amino-terminal WxxLF domain, which can interact with the AR ligand-binding domain.
“Approximately half of the ligandindependent transcriptional activity of the AR in CR prostate cancer cells is conferred by the amino-terminal WxxLF domain, which can interact with the AR LBD.”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [67]
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Self-citation
- Authors
- Dehm, S. M., Regan, K. M., Schmidt, L. J., & Tindall, D. J.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Dehm, Scott M.
- Venue
- Cancer Research
- Published
- 2007-10-15
- Volume
- 67
- Issue
- 20
- Pages
- 10067-10077
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2042646980
- Cited by
- 84
- References
- 45
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 5 · 2017: 5 · 2016: 8 · 2015: 3 · 2014: 12 · 2013: 11 · 2012: 5
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA121277, CA 91956, CA121277, P50CA091956)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065236, DK065236)
- Topics
- 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
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- androgen receptor, androgen receptor activation, NH2-terminal domain, ligand-dependent transactivation, androgen ablation resistance, prostate cancer progression, transactivation domain
- MeSH terms
- Amino Acid Sequence, Androgens, Animals, Base Sequence, Humans, Ligands, Male, Molecular Sequence Data, Prostatic Neoplasms, Receptors, Androgen, Transcriptional Activation, Protein Structure, Tertiary, Amino Acid Motifs, Mice, Androgen Receptor Antagonists
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