权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CAK-RARa Signaling in HSC and Leukemic Cell Commitment to Differentiation

HSC 和白血病细胞分化中的 CAK-RARa 信号转导

基本信息

批准号：
8204736
负责人：
LINGTAO WU
金额：
$ 31.7万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204736
关键词：
Binding Biological Assay Cell Cycle Cell Differentiation process Cell division Cell model Cells Chromatin Commit Coupled Couples Cyclins Data Development Differentiation Therapy Dissociation Environment Equilibrium Event Gene Expression Gene Targeting Genes Goals Granulopoiesis Hematopoietic Hematopoietic stem cells Human In Vitro Knowledge Leukemic Cell Ligands Mediating Molecular Myelogenous Myeloid Cells Myeloid Leukemia NOD/SCID mouse Normal Cell Phosphorylation Phosphotransferases Plant Roots Post-Translational Regulation Process Proteolysis Publishing Regulation Reporter Genes Research Role Signal Transduction Staging Structure-Activity Relationship Testing Time Transactivation Transcriptional Regulation Tretinoin Ubiquitination aldehyde dehydrogenases base cellular transduction chromatin immunoprecipitation design granulocyte improved insight leukemogenesis monocyte mutant novel prevent progenitor programs research study retinoic acid receptor alpha self-renewal small hairpin RNA spatiotemporal transcription factor

项目摘要

Aberrant differentiation is a hallmark of myeloid leukemia, reflecting a disruption of the intrinsic balance between proliferation and differentiation. Our published and preliminary data indicate that subverted RARα- CAK signaling is a pivotal feature of myeloid leukemogenesis and challenges the current paradigm that RA induces cell differentiation solely by transactivating target genes. We propose to determine how RARα-CAK signaling couples CAK-dependent G1 exit to transcriptional control of granulocytic differentiation in normal and leukemic myeloid cells. The long-term goal of our research is to provide fundamental basis for development of differentiation therapy that can force the terminal differentiation of myeloid leukemia cells. Normal cellular differentiation requires timely exit from the cell cycle. CAK, whose activity is determined by its targeting subunit MAT1, regulates cell cycle G1 exit when cells commonly commit to proliferation or to differentiation. The mechanisms by which transcription factor RARα mediates the effect of RA to coordinate the granulocytic proliferation/differentiation (P/D) transition during granulopoiesis are unknown. We discovered that, in myeloid leukemic cells, the lack of RA-induced ubiquitination-proteolysis of MAT1 inhibits CAK-dependent G1 exit and sustains CAK hyperphosphorylation of RARα to prevent granulocytic differentiation. This contrasts with the P/D transition in normal hematopoietic cells, where intrinsic MAT1 degradation proceeds together with progressive granulocytic differentiation, and the loss of RARα phosphorylation by CAK induces RA-target gene expression and granulocytic differentiation. Using in vitro cellular models and NOD/SCID mice, the proposed experiments seek to: a) evaluate the role and mechanism of MAT1 expression and degradation in normal granulopoiesis; b) evaluate the mechanisms of RA-induced ubiquitination-proteolysis of MAT1, c) determine the role and mechanism of RARα hypophosphorylation in transcriptional control of granulocytic differentiation; and d) define the role of ALDH1A1 and 1B1 in initiating RARα-CAK signaling during granulopoiesis. The proposed specific aims will examine, for the first time, the novel mechanisms by which CAK-RARα signaling coordinates CAK-dependent post-translational regulation of G1 exit to RARα-dependent transcriptional control of granulocytic differentiation. This project has the potential to generate valuable insights into the molecular regulation of granulopoiesis and therefore has clear relevance to the design of effective differentiation therapies against myeloid leukemia.

异常分化是髓系白血病的标志，反映了内在平衡的破坏在增殖和分化之间。我们发表的和初步的数据表明，颠覆RAR- CAK信号是髓系白血病发生的关键特征，并挑战了目前RA 仅通过反式激活靶基因诱导细胞分化。我们建议确定RAR-CAK 正常人粒细胞分化的转录调控与CAK依赖的G1出口信号传导偶联和白血病骨髓细胞。我们研究的长期目标是为开发可迫使髓系白血病细胞终末分化的分化疗法。正常的细胞分化需要及时退出细胞周期。CAK，其活性取决于其靶向亚基MAT 1调节细胞周期G1退出，当细胞通常致力于增殖或分化转录因子RAR介导RA协同细胞凋亡的机制粒细胞生成过程中粒细胞增殖/分化（P/D）转换是未知的。我们发现，在髓性白血病细胞中，缺乏RA诱导的MAT 1泛素化-蛋白水解抑制了 CAK依赖性G1退出并维持RAR的CAK过度磷酸化以防止粒细胞分化这与正常造血细胞中的P/D转换形成对比，其中内在MAT 1 降解与进行性粒细胞分化一起进行，并且RAR的丧失α 通过CAK的磷酸化诱导RA靶基因表达和粒细胞分化。使用体外细胞模型和NOD/SCID小鼠，所提出的实验试图：a）评估作用，正常粒细胞生成中MAT 1表达和降解的机制; B）评估MAT 1表达和降解的机制; RA诱导的MAT 1的泛素化-蛋白水解，c）确定RAR的作用和机制α 低磷酸化在粒细胞分化的转录控制中的作用;和 ALDH 1A 1和1B 1在粒细胞生成过程中启动RAR-CAK信号传导。提出的具体目标将首次研究CAK-RAR的新机制。α 信号传导协调CAK依赖的G1出口的翻译后调节，以RAR依赖粒细胞分化的转录控制。这个项目有可能产生价值对粒细胞生成的分子调控的见解，因此与设计有效的分化疗法来治疗髓性白血病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Retinoid agonist Am80-enhanced neutrophil bactericidal activity arising from granulopoiesis in vitro and in a neutropenic mouse model.

类视黄醇激动剂 Am80 增强体外粒细胞生成和中性粒细胞减少小鼠模型中的中性粒细胞杀菌活性。

DOI：
10.1182/blood-2012-06-436022
发表时间：
2013
期刊：
Blood
影响因子：
20.3
作者：
Ding,Wanjing;Shimada,Hiroyuki;Li,Lin;Mittal,Rahul;Zhang,Xiaokun;Shudo,Koichi;He,Qiaojun;Prasadarao,NemaniV;Wu,Lingtao
通讯作者：
Wu,Lingtao

Retinoid-regulated FGF8f secretion by osteoblasts bypasses retinoid stimuli to mediate granulocytic differentiation of myeloid leukemia cells.