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 RIS Download
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