摘要
NR4A1 (Nur77)、NR4A2 (Nurr1) 及NR4A3 (NOR-1)同属于NR4A 孤儿核受体亚家族。他们的激活通常比较短暂,对细胞影响是一种受刺激和细胞状态依赖引起NR4A靶向基因的差异活性,NR4A基因可以调节细胞循环、凋亡、炎症、动脉粥样硬化形成、代谢、DNA修复和肿瘤发生。NR4A1和NR4A3在急性髓系白血病(AML)中作为肿瘤抑制基因起作用。在小鼠中两个核受体的遗失会导致迅速生成AML。NR4A1 和NR4A3 的缺失是AML患者的共同特征。此外,NR4A1和NR4A3 hypoallelic小鼠—NR4A1和NR4A3表达水平下降的小鼠,发展成慢性髓系恶性肿瘤,该肿瘤包括AML稀有病例骨髓增生异常/骨髓及外骨髓增殖的肿瘤恶化的病理学特征。近期,对急性淋巴癌中NR4A1 和NR4A3 表达的下降进行了描述,并且NR4A1的低表达可能与整体存活较少有关。急性淋巴癌细胞中NR4A1的过表达会诱导异种移植物小鼠模型中的细胞凋亡和抑制肿瘤的生长。进来表明NR4A 诱导剂或NR4A 拮抗剂具有/引起AML和淋巴细胞凋亡的作用。鉴于这一事实和MR4A1、NR4A3诱导剂和NR4A拮抗剂数目的增加,两个受体均可代表抗肿瘤治疗的新靶点。
关键词: AML,凋亡,细胞周期停滞,淋巴癌,NR4A,治疗靶点,肿瘤抑制
Current Drug Targets
Title:The Nuclear Orphan Receptor NR4A1 and NR4A3 as Tumor Suppressors in Hematologic Neoplasms
Volume: 16 Issue: 1
Author(s): Kerstin Wenzl, Katharina Troppan, Peter Neumeister and Alexander J.A. Deutsch
Affiliation:
关键词: AML,凋亡,细胞周期停滞,淋巴癌,NR4A,治疗靶点,肿瘤抑制
摘要: NR4A1 (Nur77) belongs together with NR4A2 (Nurr1) and NR4A3 (NOR-1) to the nuclear orphan receptors of the NR4A-family. Their activation is generally short lived, the cellular outcome is a stimulus- and cell context-dependent differential activation of NR4A target genes that regulate cell cycle, apoptosis, inflammation, atherogenesis, metabolism, DNA repair and tumorigenesis. NR4A1 and NR4A3 were identified to function as tumor suppressors in acute myeloid leukemia (AML). Deletion of both nuclear receptors led to rapid development of AML in mice. Loss of NR4A1 and NR4A3 was a common feature in human AML patients. Additionally, NR4A1 and NR4A3 hypoallelic mice - mice with a reduced NR4A1 and NR4A3 expression - develop a chronic myeloid malignancy that recapitulates the pathological features of myelodysplastic/ myeloproliferative neoplasms with progression to AML in rare cases. Recently, a reduced NR4A1 and NR4A3 expression was described in aggressive lymphomas and low NR4A1 expression was associated with poor overall survival. Overexpression of NR4A1 in aggressive lymphoma cells led to induction of apoptosis and abrogated tumor growth in a xenograft mouse model. Recently, it was shown that NR4A inducing agents or NR4A agonist possess/induce apoptotic effects in AML and lymphoma cells. Due to this fact and the growing number of NR4A1 and NR4A3 inducing agents and NR4A agonists, both receptors represent new targets for anti tumor therapy.
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Kerstin Wenzl, Katharina Troppan, Peter Neumeister and Alexander J.A. Deutsch , The Nuclear Orphan Receptor NR4A1 and NR4A3 as Tumor Suppressors in Hematologic Neoplasms, Current Drug Targets 2015; 16 (1) . https://dx.doi.org/10.2174/1389450115666141120112818
DOI https://dx.doi.org/10.2174/1389450115666141120112818 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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