NR4A orphan nuclear receptors in immediate early regulation of retinoid signaling and neuroprotection

Abstract: NR4A receptors show distinct properties that make them unique within the family of nuclear receptors. They lack a ligand-binding cavity and a canonical coactivator-binding site and they are induced both in vivo and in vitro in an immediate early way by an extremely wide repertoire of substances/conditions. Apart from their specific roles during development, they play crucial, yet not fully charazterized, roles in sensing of and responding to changes in the cellular environment. In paper I, we provide novel insights into the mechanism of NR4A-mediated transcription by identifying an alternative coactivator-binding surface that is unique to the NR4A family of nuclear receptors. We also report a link between NR4A transcriptional activity and protein turnover and identify protein sequence differences between the NR4A receptor members that may account for their differential transcriptional activity. In paper II, we provide evidence suggesting that NR4A receptors can influence signaling events of other nuclear receptors via inducing the expression of fatty acid binding protein 5. Specifically, NR4A receptors can enhance retinoic acid-induced signaling of the peroxisome proliferator-activated receptor and docosahexaenoic acid-induced activation of the retinoid X receptor. In paper III, we demonstrate that NR4A proteins are induced by cyclic AMP response element binding protein (CREB) in neurons exposed to excitotoxic and oxidative insults and that they function as mediators of CREB-induced neuronal survival by inducing the expression of a battery of neuroprotective genes. Moreover, we show that mice with null mutations in three out of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes and increased vulnerability in the hippocampus after treatment with the excitotoxin kainic acid. In summary, we show that NR4A receptors utilize a distinct surface to bind coactivators, that they can influence signaling by two other nuclear receptors by upregulating a fatty acid binding protein and that they are essential mediators of neuroprotection after exposure to neuropathological stress.