NR4A Nuclear Receptor Function in Leukemia

该项目的总体目标是阐明核受体NOR-1和NOR-1 NUR77发挥肿瘤抑制基因的作用，以防止髓系白血病的发展。Nur77和NOR-1是 核受体转录因子NR4A亚家族的成员。NR4A受体高度 同源氨基酸序列，可与常见的顺式作用DNA元件相互作用，调节 重叠的目标基因。与大多数核受体不同，NR4A亚家族成员不是配体激活的 并且可以作为结构性活性转录因子发挥作用。此外，它们还是直销产品 早期基因，其表达和活性是以细胞特有的方式调节的，以响应各种 细胞外有丝分裂、凋亡和分化刺激。为了阐明本质上的生理学 NR4A受体的作用，我们已经产生了零突变小鼠，在其中这些蛋白的表达 被烧焦了。目前的建议是基于我们最近的发现，即小鼠同时缺乏Nur77和 NOR-1发展迅速致命性髓系白血病，Nor1/Nur77基因剂量依赖于其潜伏期 它与慢性粒细胞白血病(CML)的急性期最为相似。我们 假设Norl和Nur77是重要的肿瘤抑制转录因子 造血干细胞(HSCs)或下游髓系祖细胞及其通过通讯发挥作用 具有细胞周期成分，调节自我更新、增殖和细胞存活之间的平衡。我们 进一步假设Nor1/Nur77失活可能在推动慢性粒细胞白血病进展中起关键作用 骨髓增生性疾病进入急性期。为了验证这一假设，我们将1)继续检查细胞 Nor1/Nur77缺失突变小鼠髓系白血病的发生发展机制，2)鉴定 控制造血细胞发育的Nor1/Nur77依赖的分子遗传信号通路，3) 确定Nor1/Nur77缺失是否与bcr-abl致癌信号协同驱动急性期 在CML小鼠模型中的进展，以及4)确定Norl和Nur77的转基因靶向是否 髓系祖细胞足以挽救Nor1/Nur77缺失小鼠的白血病表型。

The overall objective of this project is to elucidate the mechanisms by which the nuclear receptors nor-1 and nur77 function as tumor suppressors to prevent the development of myeloid leukemia. Nur77 and nor-1 are members of the NR4A subfamily of nuclear receptor transcription factors. NR4A receptors have highly homologous amino acid sequences and can interact with common cis-acting DNA elements to regulate overlapping target genes. Unlike most nuclear receptors, NR4A subfamily members are not ligand activated and can function as constitutively active transcription factors. In addition, they are products of immediate early genes whose expression and activity are regulated in a cell specific manner in response to a variety of extracellular mitogenic, apoptotic and differentiative stimuli. In order to elucidate the essential physiological roles of NR4A receptors, we have generated null mutant mice in which the expression of these proteins has been ablated. The current proposal is based on our recent discovery that mice deficient in both nur77 and nor-1 develop rapidly lethal myeloid leukemia that is nor1/nur77 gene dosage dependent in its latency of development and most closely resembles the acute phase of chronic myeloid leukemia (CML). We hypothesize that norl and nur77 are essential tumor suppressor transcription factors operating most likely in hematopoietic stem (HSCs) or downstream myeloid progenitor cells and exert their effects by communication with cell cycle components to regulate the balance between serf renewal, proliferation and cell survival. We further hypothesize that inactivation of nor1/nur77 may play a key role in driving progression of chronic myeloproliferative disease to acute phase. To test this hypothesis, we will 1) continue to examine the cellular mechanisms of initiation and progression of myeloid leukemia in nor1/nur77 null mutant mice, 2) identify the nor1/nur77 dependent molecular genetic signaling pathways that control myelopoietic cell development, 3) determine whether loss of nor1/nur77 cooperates with BCR-ABL oncogenic signaling to drive acute phase progession in a mouse model of CML, and 4) determine whether transgenic targeting of norl and nur77 to myeloid progenitor cells is sufficient to rescue the leukemic phenotype in nor1/nur77 null mice.