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The androgen receptor: a mediator of diverse responses
E T Keller1, W B Ershler, C Chang
1The Institute on Aging and the Department of Human Oncology, University of Wisconsin, Madison, WI 53706, USA.
Abstract:
Androgens mediate a number of diverse responses through the androgen receptor, a 110 kD ligand-activated nuclear receptor. Androgen receptor expression, which is found in a variety of tissues, changes throughout development, aging, and malignant transformation. The androgen receptor can be activated by two ligands, testosterone and dihydrotestosterone, which bind to the androgen receptor with different affinities. This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands. The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element. The ability to confer androgen specific actions by the androgen response element may depend on other cell-specific transcription factors and cis-acting DNA elements in close proximity to it. Testosterone and dihydrotestosterone appear to act upon an identical nuclear receptor. However, in certain instances, they mediate different physiologic responses. For example, dihydrotestosterone, but not testosterone, is capable of mediating full sexual development of the male external genitalia. In some cases, the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location. For example, in male pattern baldness, activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal-epithelial actions, whereas other hair follicles continue to proliferate. In other cases, altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation.
Insights
Androgens, like testosterone, activate the androgen receptor (AR) to control gene expression. Differences in AR activation by androgens lead to varied physiological responses and can cause diseases like prostate cancer.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Androgens exert diverse effects via the androgen receptor (AR), a ligand-activated nuclear receptor.
- AR expression varies across tissues and changes with development, aging, and cancer.
- Testosterone and dihydrotestosterone are AR ligands with differing binding affinities, influencing AR activation levels.
Purpose of the Study:
- To elucidate the mechanisms by which androgens and the androgen receptor regulate gene expression.
- To explore how differential ligand binding affects AR activity and physiological outcomes.
- To understand the role of AR in normal development and disease, including cancer.
Main Methods:
- Analysis of androgen receptor (AR) structure and function.
- Investigation of AR binding to androgen response elements (AREs).
- Examination of AR-mediated gene transcription in various cellular contexts.
Main Results:
- AR acts as a transcriptional modifier, binding to AREs to regulate target genes.
- Differential affinities of testosterone and dihydrotestosterone for AR result in distinct activation levels.
- AR can mediate opposing physiological effects, as seen in male sexual development and male pattern baldness.
Conclusions:
- The androgen receptor plays a critical role in mediating androgen-specific actions.
- Variations in AR activity, influenced by ligands and cellular context, underlie diverse physiological responses.
- Dysregulation of AR signaling contributes to pathologies, including the recurrence of prostate cancer through androgen independence.