Molecular Mechanisms of Acute Promyelocytic Leukemia

急性早幼粒细胞白血病的分子机制

• 批准号: 6774426
• 负责人: Ananda L Roy
• 金额: $ 7.93万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774426
• 关键词: RNA interference; biological signal transduction; cell cycle; cell growth regulation; cell line; fos protein; interferons; myelogenous leukemia; posttranslational modifications; protein protein interaction; protein structure function; protooncogene; transcription factor

DESCRIPTION (provided by applicant): The promyelocytic leukemia (PML) gene codes for a tumor suppressor protein that is associated with distinct subnuclear macromolecular structures called the PML bodies. The PML gene is frequently involved in the t (15;17) chromosomal translocation of acute promyelocytic leukemia (APL). The translocation results in a fusion gene product, PML-RARalpha, in which the PML gene fuses to the retinoic acid receptor alpha (RARalpha) gene. PML-RARa behaves as a potent transcriptional repressor for apoptotic genes and disrupts the architecture of PML bodies, a phenotype reversed by treatment with all trans retinoic acid (ATRA). Besides its role in APL, PML bodies have also been linked to viral infection. A variety of viruses targets the nuclear bodies and often causes their disruption. Moreover, upon interferon treatment of normal cells, PML is induced and the number of PML bodies increases dramatically, suggesting that PML may function as a mediator of interferon function and behaves as an immune surveillance factor. Although the activities of several transcription factors are modulated by virtue of physical association with PML bodies, the molecular mechanisms of PML or PML-RARalpha-mediated gene regulation remain elusive. Given the biological importance of PML and PML-RARalpha proteins, it is critical to ascertain their functional role and mechanisms of action. The TFII-I family of multifunctional transcription factors is activated in response to growth factor and antigenic signals to regulate growth-controlling genes, thus linking signal transduction events to transcription. We show a novel association of TFII-I family of factors with PML bodies. We further show a previously unknown function for PML-RARalpha it hyper-activates c-fos promoter in response to growth factor signaling. Based on these and other results, we hypothesize that the growth-regulatory and antigenic signals are processed through PML bodies in normal and APL cells to activate genes that control cellular growth or death via TFII-I family proteins. We propose to elucidate this novel pathway that will lead to a better understanding of PML and PML-RARalpha function.

描述(由申请人提供)：早幼粒细胞白血病(PML)基因编码一种肿瘤抑制蛋白，该蛋白与称为PML小体的不同亚核大分子结构相关。PML基因常与急性早幼粒细胞白血病(APL)t(15；17)染色体易位有关。易位导致融合基因产物PML-RARpha，其中PML基因与维甲酸受体α(RARpha)基因融合。PML-RARA作为一种有效的转录抑制因子作用于凋亡基因，并破坏PML小体的结构，这种表型被全反式维甲酸(ATRA)处理逆转。除了在急性早幼粒细胞白血病中的作用外，PML小体也与病毒感染有关。各种各样的病毒以核体为目标，并经常造成它们的破坏。此外，当干扰素作用于正常细胞时，PML被诱导，PML小体数量急剧增加，提示PML可能作为干扰素功能的介体，并作为免疫监视因子发挥作用。尽管一些转录因子的活性是通过与PML小体的物理结合来调节的，但PML或PML-RARpha介导的基因调控的分子机制仍然不清楚。鉴于PML和PML-RARpha蛋白的生物学重要性，确定它们的功能作用和作用机制至关重要。 多功能转录因子TFII-I家族在生长因子和抗原信号的作用下被激活，从而调节生长控制基因，从而将信号转导事件与转录联系起来。我们发现了一种新的TFII-I因子家族与PML小体的关联。我们进一步展示了PML-RARpha的一个以前未知的功能，它在响应生长因子信号转导时过度激活c-fos启动子。基于这些和其他结果，我们假设生长调节和抗原信号是通过正常和APL细胞中的PML小体来处理的，以激活通过TFII-I家族蛋白控制细胞生长或死亡的基因。我们建议阐明这一新的途径，这将导致对PML和PML-RARpha功能的更好理解。