NR4A1, 2, 3--an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis

Three members of the NR4A1/Nur77/ NGFIB orphan nuclear hormone receptor subfamily (NR4A1, NR4A2, and NR4A3) belong to the steroid nuclear hormone receptor superfamily. They share similar structural features and have no known natural ligand. They constitute immediate early genes that are induced by serum, growth factors and receptor engagement and are thus implicated in cell mitogenic responses. These nuclear receptors are transcription factors that exert their functions through activation and subsequent induction of the downstream pathways. They have been shown to play a role in complex pathways of cell survival and apoptosis. Although the expression of these genes have been shown to be pro-survival, it has also been reported that NR4A1 expression can cause apoptosis. These two opposite effects apparently result from distinct mechanisms: either transcriptional activation of genes responsible for cell survival or cell apoptosis, or translocation into the cytoplasm where they target the mitochondria and cause cell apoptosis via Bcl-2 binding. The latter mechanism constitutes a new paradigm of cellular apoptosis. In vitro functional studies using over-expression (gain of function) or gene inactivation (loss of function) type assays, combined with transgenic or knockout animal data in vivo, have revealed these effects and their physiological roles, including thymocyte development for NR4A1/3 and pro-survival in CNS for NR4A2. Recent studies have also suggested an important role of these receptors in cell transformation and tumorigenicity via both their anti-apoptotic and pro-apoptotic functions. In particular, the recent identification of a functional ligand for NR4A1 suggests that these members could potentially serve as drug targets for disease indications such as cancer. While many aspects of these receptors have been previously reviewed, this article focuses on new experimentation and discovery of their apoptotic and carcinogenic roles, and discusses their potential roles as therapeutic targets.