Post-Translational Modifications of Nuclear Receptors and Human Disease

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.

Targeting the glucocorticoid receptor in breast and prostate cancers

“…As a new generation of more selective GR antagonists becomes available, decreased drug-drug interactions and increased GR specificity are expected. Regulation and function of tumor GR in the natural history of tumor development, including identifying downstream GR target genes, understanding GR’s chromatin remodeling ability, and characterizing dynamic interactions with other nuclear hormone receptors, coactivators, and repressors will be explored (13, 18, 19, 32–34). A better understanding of GR-regulated resistance to cytotoxicity may reveal other targetable pathways.…”

Inhibition by Female Sex Hormones of Collagen Gel Contraction Mediated by Retinal Pigment Epithelial Cells

“…We detected the expression of both ER and PR in cultured mouse RPE cells. Both receptors are also regulated by posttranslational modification such as ubiquitination, phosphorylation, and acetylation, [60][61][62] adding an additional level of complexity to regulation of the actions of female sex hormones.…”

Glucocorticoid resistance as a major drive in sepsis pathology

“…alternative methionine start codons, have been identified in GR mRNA molecules, resulting in eight hGRα subtype of proteins [36]. Finally, numerous post-translational modifications of the GR protein have been described to influence its biological activity [37,38].…”