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.

Figure 1. Phosphorylation sites in nuclear receptors.

Nuclear receptor function is regulated in large part by post-translational modification, including phosphorylation. Phosphorylation occurs on serine (S), threonine (T) and tyrosine (Y) residues. AF-1- Activation Function-1; DBD- DNA Binding Domain; AF-2- Activation Function-2; LBD- Ligand Binding Domain.

Figure 2. Sumoylation and ubiquitination of the androgen receptor are involved in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy is caused by an abnormally high number of CAG trinucleotide repeats that encode for a stretch of uninterrupted polyglutamine amino acids in the AR known as a polyglutamine tract or polyQ tract. (A) Sumoylation of the androgen receptor has been shown to reduce aggregates of polyQ and occurs at lysine residues 386 and 520. (B) Overexpression of carboxyl terminus of Hsp70-interacting protein (CHIP), an ubiquitin E3 ligase, leads to ubiquitination of mutant AR, providing protection from SBMA.

Figure 3. Acetylation of androgen receptor.

(A) Acetylation of AR occurs at lysine residues 630, 632, and 633 and is mediated by interactions with coregulators with intrinsic histone acetyltransferase (HAT) activity, such as coactivators p300, P/CAF and TIP60 (Tat-interactive protein). (B) Acetylation mimicking mutants (K630Q/K630T) exhibited increased cell growth in prostate cancer cell lines.

Figure 4. Acetylation of estrogen receptor α.

(A) Acetylation of the estrogen receptor α requires the interaction of the receptor and of coregulators such as p300 that possess intrinsic histone acetyltransferase (HAT) activity. (B) Mutation of lysine residues 302/303 to arginine, rendering these sites incapable of being acetylated, resulted in hypersensitivity to estradiol in breast cancer cell lines.

Figure 5. Estrogen receptor α sumoylation and ubiquitination.

(A) Sumoylation of ERα occurs at lysine residues 266 and 268 (K266 and K268). (B) Unstimulated estrogen receptor is ubiquitinated and degraded by carboxyl terminus of Hsp70-interacting protein (CHIP), an ubiquitin E3 ligase. Fulvestrant (ICI 182,780), a pure anti-estrogen, utilizes the ubiquitination mechanism to induce proteasome-dependent degradation of ERα.

Figure 6. GR regulation of inflammatory genes.

Upon ligand binding, the GR translocates to the nucleus, is acetylated by HATs, and binds to Glucocorticoid Response Elements (GRE) to induce transcription of anti-inflammatory genes. The liganded GR can also functionally repress NF-κB-mediated pro-inflammatory genes.

Figure 7. Sumoylation of PPARγ and transcriptional repression of inflammatory genes.

Sumoylation of PPARγ promotes interaction with a transcriptional repression complex at NF-κB gene promoters preventing release and turnover of the repression complex, thereby maintaining repression of inflammatory genes.