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.
Lin
Bingzhen
B
The Burnham Institute, Cancer Center, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Kolluri
Siva Kumar
SK
Lin
Feng
F
Liu
Wen
W
Han
Young-Hoon
YH
Cao
Xihua
X
Dawson
Marcia I
MI
Reed
John C
JC
Zhang
Xiao-kun
XK
D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; D008024:Ligands; D008164:Luminescent Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D005982:Glutathione Transferase