Related Experiment Video

Updated: Oct 17, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation

S Hauser1, G Adelmant, P Sarraf

  • 1Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|April 5, 2000
PubMed

Insights

Ligand activation of peroxisome proliferator-activated receptor (PPAR) gamma, crucial for glucose homeostasis and diabetes treatment, leads to its degradation. This process involves ubiquitination and proteasome pathways, independent of transcriptional activity but dependent on the AF2 domain.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Biochemistry

Background:

  • Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear hormone receptor regulating adipogenesis and glucose homeostasis.
  • It serves as the functional receptor for thiazolidinediones, a class of drugs used to treat type 2 diabetes mellitus.

Purpose of the Study:

  • To investigate the effect of specific ligands on PPARgamma protein levels.
  • To elucidate the mechanism of PPARgamma regulation by its ligands.

Main Methods:

  • Treatment of adipose cells and fibroblasts with various ligands.
  • Analysis of PPARgamma protein levels and ubiquitination.
  • Studies using PPARgamma mutants and proteasome inhibitors.

Main Results:

  • Ligand activation, including thiazolidinediones, significantly reduces PPARgamma protein levels.
  • PPARgamma degradation correlates with ligand-induced receptor activation.
  • Degradation is dependent on the activation function 2 (AF2) domain but not strictly on transcriptional activity.
  • Proteasome inhibitors block PPARgamma down-regulation, and ligand activation enhances its ubiquitination.

Conclusions:

  • Ligand binding and AF2 domain activation of PPARgamma induce its ubiquitination and subsequent proteasomal degradation.
  • This degradation pathway is a critical regulatory mechanism for PPARgamma function, impacting its role in biological processes and therapeutic applications.

Related Concept Videos

GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
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:
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
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...
Peroxisomes01:24

Peroxisomes

Peroxisomes are specialized organelles present in fungi, plant, and animal cells. It can vary in number, size, morphology, and activity depending on the type of tissue and the nutritional state of the cell. For example, cells with active lipid metabolism, such as adipocytes, neurons, and hepatocytes, have more peroxisomes than other cells in the body. Besides their primary role in breaking down complex organic molecules, peroxisomes can also synthesize specific macromolecules and participate in...