Mullican Shannon E, Zhang Shuo, Konopleva Marina, Ruvolo Vivian, Andreeff Michael, Milbrandt Jeffrey, Conneely Orla M
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nat Med. 2007 Jun;13(6):730-5. doi: 10.1038/nm1579. Epub 2007 May 21.
Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors that regulate the transcription of overlapping target genes. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals. Cellular responses to these proteins suggest that they may function as homeostatic regulators of proliferation, apoptosis and differentiation, and thus may regulate cellular susceptibility to tumorigenesis. Their physiological functions, however, remain poorly understood. Here we describe a previously unsuspected function of Nor-1 and Nur77-as critical tumor suppressors of myeloid leukemogenesis. The abrogation of these proteins in mice led to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, decreased expression of the AP-1 transcription factors JunB and c-Jun and defective extrinsic apoptotic (Fas-L and TRAIL) signaling. We found that downregulation of NR4A3 ( NOR-1 ) and NR4A1 ( NUR77 ) was a common feature in leukemic blasts from human AML patients, irrespective of karyotype. Thus Nor-1 and Nur77 may provide potential targets for therapeutic intervention in AML.
Nur77（NR4A1）和Nor-1（NR4A3）是高度同源的孤儿核受体，它们调控重叠靶基因的转录。这两种蛋白质的转录活性通过细胞和刺激特异性基因诱导以及蛋白质磷酸化以不依赖配体的方式进行调控。Nor-1和Nur77参与了多种细胞过程，包括激素、炎症、有丝分裂原、凋亡和分化信号的转导。细胞对这些蛋白质的反应表明它们可能作为增殖、凋亡和分化的稳态调节因子发挥作用，因此可能调节细胞对肿瘤发生的易感性。然而，它们的生理功能仍知之甚少。在此，我们描述了Nor-1和Nur77一个先前未被怀疑的功能——作为髓系白血病发生的关键肿瘤抑制因子。在小鼠中缺失这些蛋白质会导致快速致死的急性髓系白血病（AML），涉及造血干细胞（HSC）和髓系祖细胞的异常扩增、AP-1转录因子JunB和c-Jun的表达降低以及外源性凋亡（Fas-L和TRAIL）信号缺陷。我们发现，NR4A3（NOR-1）和NR4A1（NUR77）的下调是人类AML患者白血病原始细胞中的一个共同特征，与核型无关。因此，Nor-1和Nur77可能为AML的治疗干预提供潜在靶点。
