Li Q-X, Ke N, Sundaram R, Wong-Staal F
Immusol, Inc., San Diego, CA, USA.
Histol Histopathol. 2006 May;21(5):533-40. doi: 10.14670/HH-21.533.
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.
NR4A1/Nur77/NGFIB孤儿核激素受体亚家族的三个成员（NR4A1、NR4A2和NR4A3）属于类固醇核激素受体超家族。它们具有相似的结构特征，且尚无已知的天然配体。它们构成即刻早期基因，可被血清、生长因子和受体结合所诱导，因此与细胞有丝分裂反应有关。这些核受体是转录因子，通过激活并随后诱导下游途径发挥其功能。已表明它们在细胞存活和凋亡的复杂途径中发挥作用。尽管这些基因的表达已显示具有促存活作用，但也有报道称NR4A1的表达可导致细胞凋亡。这两种相反的作用显然源于不同的机制：要么是负责细胞存活或细胞凋亡的基因的转录激活，要么是转位到细胞质中，在那里它们靶向线粒体并通过与Bcl-2结合导致细胞凋亡。后一种机制构成了细胞凋亡的新范式。使用过表达（功能获得）或基因失活（功能丧失）类型的实验进行的体外功能研究，结合体内的转基因或基因敲除动物数据，揭示了这些作用及其生理功能，包括NR4A1/3对胸腺细胞发育的作用以及NR4A2对中枢神经系统的促存活作用。最近的研究还表明，这些受体通过其抗凋亡和促凋亡功能在细胞转化和肿瘤发生中发挥重要作用。特别是，最近发现了NR4A1的功能性配体，这表明这些成员有可能作为癌症等疾病适应症的药物靶点。虽然这些受体的许多方面此前已有综述，但本文重点关注其凋亡和致癌作用的新实验和发现，并讨论它们作为治疗靶点的潜在作用。
