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.

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.

Related Concept Videos

Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
Signal Transduction: Overview01:26

Signal Transduction: Overview

Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
Typically, signal transduction involves three...
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
Regulation of Expression at Multiple Steps01:23

Regulation of Expression at Multiple Steps

The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the addition of a...