citations

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

Authors:

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

In:

Source: Cell
Publication Date: (2004)
Issue: 116(4): 527-540

Research Area:

Immunotherapy / Hematology

Cells used in publication:

PBMC, human: Species: human; Tissue Origin: blood

Platform:

Nucleofector® I/II/2b

Experiment

The authors wanted to extend their findings from work with cell lines to primary cells, i.e. cells that are much closer to the in-vivo situation. This was possible by using nucleofection. For localization studies, primary human peripheral blood cells (PBLs) were co-transfected with a plasmid coding for GFP-Nur77 and a plasmid coding for a red fluorescent protein fused to a mitochondria-targeting sequence. A plasmid encoding a GFP fusion of another Nur77 variant, as well as Nur77 siRNA and Bcl-2 antisense were nucleofected into PBLs to examine the effects on apoptosis.

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.

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