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

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.

Pubmed ID: 14980220

Authors

  • Lin B
  • Kolluri SK
  • Lin F
  • Liu W
  • Han YH
  • Cao X
  • Dawson MI
  • Reed JC
  • Zhang XK

Journal

Cell

Publication Data

February 20, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: CA60988
  • Agency: NCI NIH HHS, Id: CA87000
  • Agency: NIGMS NIH HHS, Id: GM60554

Mesh Terms

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