New Insights into the Diverse Functions of the NR2F Nuclear Orphan Receptor Family

Following gene expansion during evolution, today's phylogenetic tree of the NR2F family of nuclear orphan receptors in mammals is represented by three different isoforms: NR2F1, NR2F2, and NR2F6. Structural analysis of the NR2F family members has revealed that NR2F1 and NR2F2 are closely related and grouped together apart from NR2F6, which is more divergent in its biochemical characteristics. In this review, we highlight current knowledge on the cellular functions of NR2F family members. NR2F family members have been reported to be causally involved in carcinogenesis. Mechanistically, NR2F proteins are localized in the nucleus, where they bind to target DNA enhancer sequences and have been implicated in the regulation of de novo gene transcription, though this is not sufficiently understood. Based on apparently divergent and non-uniform expression patterns of the NR2F isoforms in different tissues and cell types, non-redundant functions of the individual family members appear to exist. Notably, NR2F2 appears to be more closely related functionally to NR2F6 than NR2F1. Along these lines, NR2F2 and NR2F6 have been reported to be involved in cellular neoplasia. Furthermore, enhanced expression of NR2F isoforms has been established as prognostic biomarkers in various cancer entities. Therefore, it is tempting to speculate that NR2F isoforms represent innovative targets for therapeutic intervention in defined types of cancer. Thus, NR2F family nuclear receptors can be viewed as gatekeepers balancing cell type-specific regulation of proliferation and the suppression of terminal differentiation in health and disease.