Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3

Cell. 2004 Feb 20;116(4):527-40. doi: 10.1016/s0092-8674(04)00162-x.

Abstract

The Bcl-2 family proteins are key regulators of apoptosis in human diseases and cancers. Though known to block apoptosis, Bcl-2 promotes cell death through an undefined mechanism. Here, we show that Bcl-2 interacts with orphan nuclear receptor Nur77 (also known as TR3), which is required for cancer cell apoptosis induced by many antineoplastic agents. The interaction is mediated by the N-terminal loop region of Bcl-2 and is required for Nur77 mitochondrial localization and apoptosis. Nur77 binding induces a Bcl-2 conformational change that exposes its BH3 domain, resulting in conversion of Bcl-2 from a protector to a killer. These findings establish the coupling of Nur77 nuclear receptor with the Bcl-2 apoptotic machinery and demonstrate that Bcl-2 can manifest opposing phenotypes, induced by interactions with proteins such as Nur77, suggesting novel strategies for regulating apoptosis in cancer and other diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis
  • Cell Death
  • Cell Line
  • Cytochromes c / metabolism
  • DNA-Binding Proteins / metabolism*
  • Glutathione Transferase / metabolism
  • Green Fluorescent Proteins
  • Humans
  • Ligands
  • Luminescent Proteins / metabolism
  • Lymphocytes / metabolism
  • Microscopy, Fluorescence
  • Mitochondria / metabolism
  • Mutation
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Oligonucleotides, Antisense / pharmacology
  • Phenotype
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA, Small Interfering / metabolism
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors / metabolism*
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • DNA-Binding Proteins
  • Ligands
  • Luminescent Proteins
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • Green Fluorescent Proteins
  • Cytochromes c
  • Glutathione Transferase