NR4A Nuclear Receptor Function in Leukemia

本项目的总体目标是阐明核受体nor-1和 NUR 77作为肿瘤抑制剂起作用以防止髓性白血病的发展。Nur-77和Nor-1是 核受体转录因子NR 4A亚家族成员。NR 4A受体具有高度的 同源氨基酸序列，并可与常见的顺式作用DNA元件相互作用，以调节 重叠靶基因。与大多数核受体不同，NR 4A亚家族成员不是配体激活的 并且可以作为组成型活性转录因子发挥作用。此外，它们是直接 早期基因，其表达和活性以细胞特异性方式响应于多种 细胞外促有丝分裂、凋亡和分化刺激。为了阐明基本的生理 为了研究NR 4A受体的作用，我们已经产生了无效突变小鼠，其中这些蛋白质的表达具有 被消融了。目前的建议是基于我们最近的发现，即nur 77和 nor-1发展为快速致死性髓系白血病，其潜伏期依赖于nor 1/nur 77基因剂量。 慢性粒细胞性白血病（CML）是一种慢性粒细胞性白血病（CML）。我们 假设norl和nur 77是最有可能在 造血干细胞（HSC）或下游骨髓祖细胞，并通过通讯发挥其作用 与细胞周期组分一起调节自我更新、增殖和细胞存活之间的平衡。我们 进一步假设nor 1/nur 77的失活可能在驱动慢性炎症进展中起关键作用， 骨髓增生性疾病急性期。为了验证这一假设，我们将1）继续检查细胞 在nor 1/nur 77无效突变小鼠中髓性白血病的起始和进展机制，2）鉴定 nor 1/nur 77依赖的控制骨髓细胞发育的分子遗传信号通路，3） 确定nor 1/nur 77的缺失是否与BCR-ABL致癌信号传导协同作用以驱动急性期 4）确定norl和nur 77在CML小鼠模型中的转基因靶向作用是否与CML小鼠模型中的表达相关，以及 髓样祖细胞足以挽救NOR 1/Nur 77缺失小鼠中的白血病表型。

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.