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

By B. Lin, S. Kolluri, F. Lin, Wen Liu, Young-Hoon Han, Xihua Cao, M. Dawson, John Calvin Reed, Xiao-kun Zhang. Cell, 2004

680 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/de5bea8e27eb534536ba172fb6afd3f6b0532d12

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Redox Regulation of Cell Survival (2008, positive): “Interestingly, recent work showed that conformational change of Bcl-2 through its binding with Nur77 can convert Bcl-2 to a proapoptotic protein (185).”
Bcl-2 family proteins and cancer (2008, background): “…can be induced to translocate from nucleus to cytosol, binding Bcl-2, and inducing a conformational change in Bcl-2 that probably mimics what happens during caspase cleavage, exposing the normally buried BH3 domain of Bcl-2 and causing it to function as a proapoptotic protein (Lin et al., 2004).”
The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and survival of Ly6C− monocytes (2011, neutral): “Consistent with its role as a mediator of apoptosis in lymphocytes, NR4A1 triggers mitochondrial apoptosis though its interaction with Bcl-2, converting Bcl-2 from an antiapoptotic molecule to a proapoptotic molecul”
Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy (2006, background): “Moreover, the orphan nuclear receptor Nur77 (also known as TR3) has recently been coupled with the Bcl-2 apoptotic machinery at the mitochondria (Lin et al., 2004).”