Related Experiment Video

Updated: Aug 21, 2026

Optimized Automated Analysis of Live Neuronal Mitochondria Homeostasis Modulation by Isoform-Specific Retinoic Acid Receptors
08:33

Optimized Automated Analysis of Live Neuronal Mitochondria Homeostasis Modulation by Isoform-Specific Retinoic Acid Receptors

Published on: July 28, 2023

Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and

Xihua Cao1, Wen Liu, Feng Lin

  • 1The Burnham Institute, Cancer Center, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.

Molecular and Cellular Biology
|October 29, 2004
PubMed

Insights

Retinoid X receptor alpha (RXRalpha) facilitates the nuclear export and mitochondrial targeting of Nur77, a key step in apoptosis. RXRalpha ligands and heterodimerization inhibit this process, revealing a new role for RXRalpha in regulating cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Retinoid X receptor (RXR) is a crucial regulator of intracellular signaling pathways.
  • RXR acts as a heterodimerization partner for various nuclear receptors, including Nur77.
  • Nur77 translocates to mitochondria to induce apoptosis via Bcl-2 interaction.

Purpose of the Study:

  • To investigate the role of RXRalpha in the nuclear export and mitochondrial targeting of Nur77.
  • To elucidate the mechanism of RXRalpha-mediated regulation of Nur77-induced apoptosis.
  • To identify a novel nongenotropic function of RXRalpha.

Main Methods:

  • Investigated RXRalpha-Nur77 heterodimerization using dimerization interfaces in their DNA-binding domains.
  • Identified a nuclear export sequence (NES) in RXRalpha's carboxyl-terminal region.
  • Examined the effects of RXRalpha ligands and heterodimerization with other nuclear receptors (RAR, VDR) on NES activity and apoptosis.

Main Results:

  • RXRalpha is essential for Nur77 nuclear export and mitochondrial translocation via heterodimerization.
  • RXRalpha's NES activity is suppressed by homodimerization or heterodimerization with RAR/VDR, and by RXRalpha ligands.
  • RXR ligands inhibit the mitochondrial targeting of the RXRalpha/Nur77 heterodimer and its apoptotic function.

Conclusions:

  • RXRalpha plays a critical role in regulating Nur77-dependent apoptosis through a nongenotropic mechanism.
  • Heterodimerization and ligand binding modulate RXRalpha's function in controlling Nur77 localization and apoptotic signaling.
  • This study uncovers a novel pathway where RXRalpha influences programmed cell death independent of its transcriptional activity.

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:
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...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
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...