Post-translational modifications of nuclear receptors and human disease
Muralidharan Anbalagan1, Brandy Huderson, Leigh Murphy
1Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Abstract:
Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARγ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.
Insights
Nuclear receptor (NR) post-translational modifications (PTMs) significantly influence physiological processes and disease development. PTMs like phosphorylation, acetylation, and sumoylation of key NRs are crucial biomarkers for disease progression and treatment response.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Nuclear receptors (NRs) regulate vital physiological functions, including metabolism and homeostasis.
- Post-translational modifications (PTMs) critically control NR activity and function.
- Aberrant NR PTMs are increasingly implicated in the pathogenesis of various human diseases, notably cancer.
Purpose of the Study:
- To review the role of PTMs in NR function.
- To highlight the association of NR PTMs with human diseases, particularly cancer.
- To explore the potential of NR PTMs as biomarkers for disease and treatment response.
Main Methods:
- Literature review focusing on studies investigating NR PTMs.
- Analysis of evidence linking specific PTMs (phosphorylation, acetylation, sumoylation) of key NRs (AR, ERα, GR, PPARγ) to disease.
- Evaluation of PTMs as potential diagnostic and predictive markers.
Main Results:
- Phosphorylation, acetylation, and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR), and peroxisome proliferator activated receptor γ (PPARγ) are linked to various diseases.
- Specific PTMs of AR, ERα, GR, and PPARγ correlate with cancer progression, treatment outcomes (e.g., tamoxifen therapy), and metabolic/inflammatory conditions.
- NR PTMs demonstrate potential as biomarkers for disease status and patient response to therapies.
Conclusions:
- NR PTMs are critical regulators of NR function with significant implications in human health and disease.
- The study of NR PTMs offers valuable insights into disease mechanisms and identifies potential therapeutic targets.
- NR PTMs serve as promising biomarkers for predicting disease progression and guiding patient treatment strategies.
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