NR4A Nuclear Receptor Function in Leukemia

NR4A 核受体在白血病中的功能

• 批准号: 7050049
• 负责人: ORLA M. CONNEELY
• 金额: $ 26.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-18 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050049
• 关键词: apoptosis; biological signal transduction; cell growth regulation; cell proliferation; chimeric proteins; chronic myelogenous leukemia; flow cytometry; gene expression profiling; gene targeting; genetic regulation; genetically modified animals; hematopoiesis; hematopoietic stem cells; hematopoietic tissue transplantation; laboratory mouse; loss of heterozygosity; microarray technology; molecular oncology; myeloid stem cell; neoplasm /cancer genetics; neoplastic transformation; nuclear receptors; oncoproteins; phenotype; polymerase chain reaction; protein structure function; single strand conformation polymorphism; southern blotting; stem cell transplantation; tumor suppressor proteins

DESCRIPTION (provided by applicant): 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 nor1 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 progression in a mouse model of CML, and 4) determine whether transgenic targeting of nor1 and nur77 to myeloid progenitor cells is sufficient to rescue the leukemic phenotype in nor1/nur77 null mice.

描述（由申请人提供）：本项目的总体目标是阐明核受体nor-1和nur77作为肿瘤抑制因子预防髓性白血病发展的机制。Nur77和nor-1是核受体转录因子NR4A亚家族的成员。NR4A受体具有高度同源的氨基酸序列，可与常见的顺式作用DNA元件相互作用，调控重叠的靶基因。与大多数核受体不同，NR4A亚家族成员不是配体激活的，可以作为组成型活性转录因子发挥作用。此外，它们是即时早期基因的产物，其表达和活性以细胞特异性的方式调节，以响应各种细胞外有丝分裂、凋亡和分化刺激。为了阐明NR4A受体的基本生理作用，我们产生了零突变小鼠，其中这些蛋白的表达已被清除。目前的建议是基于我们最近的发现，缺乏nur77和nor-1的小鼠会发生快速致死性髓性白血病，其发展潜伏期依赖于nor1/nur77基因的剂量，与慢性髓性白血病（CML）的急性期最相似。我们推测，nor1和nur77是最可能在造血干细胞（hsc）或下游髓系祖细胞中发挥作用的重要肿瘤抑制转录因子，并通过与细胞周期成分的交流发挥作用，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的失活可能在推动慢性骨髓增生性疾病进展到急性期中发挥关键作用。为了验证这一假设，我们将1)继续研究nor1/nur77零突变小鼠骨髓性白血病发生和进展的细胞机制，2)鉴定控制骨髓细胞发育的nor1/nur77依赖分子遗传信号通路，3)确定nor1/nur77缺失是否与BCR-ABL致癌信号共同驱动CML小鼠模型的急性期进展。4)确定nor1和nur77转基因靶向骨髓祖细胞是否足以挽救nor1/nur77缺失小鼠的白血病表型。