Mechanism of Action of Retinoic Acid Using CD38

视黄酸利用 CD38 的作用机制

基本信息

批准号：
8878194
负责人：
Quan Hao
金额：
$ 32.54万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878194
关键词：
Acute Promyelocytic Leukemia Binding Biological Models Calcium Catalytic Domain Cell Cycle Arrest Cell Differentiation process Cell Line Cells Chemopreventive Agent Chemotherapy-Oncologic Procedure Cholecalciferol Complex Cyclic ADP-Ribose Diet Dimerization Disease remission Dose Effectiveness Gene Expression Goals Growth Health Human Intervention Investigation Laboratories M2 Acute Myeloid Leukemia MAP Kinase Gene Malignant Neoplasms Molecular Myelogenous Myeloid Leukemia NAADP NADP Nature Neoadjuvant Therapy Neoplastic Cell Transformation Niacinamide Outcome Patients Phenotype Process Production RXR Reagent Receptor Signaling Reporting Research Personnel Roentgen Rays Role Sampling Second Messenger Systems Signal Transduction Signaling Molecule Structure Sum Surveys Tail Transcriptional Regulation Tretinoin Vitamin A Work base cell transformation dimer innovation insight interest leukemia mutant neoplastic novel precursor cell programs prohormone receptor receptor expression second messenger small hairpin RNA small molecule

项目摘要

DESCRIPTION (provided by applicant): This is a multi-investigator proposal to study a novel means of enhancing the mechanism by which retinoic acid (RA) causes growth arrest and differentiation by exploiting RA-induced expression and signaling by the CD38 receptor. RA is a cancer chemopreventive agent. It is a prohormone provided in the diet and is a common dietary insufficiency. RA can convert immature neoplastically transformed cells to a mature differentiated phenotype. The proposed studies utilize immature, uncommitted human leukemia granulocytic-monocytic precursor cells which undergo G0 arrest and either myeloid or monocytic differentiation when treated with RA or vitamin D3 (D3) respectively. RA causes activation of MAPK signaling in the process of inducing terminal myeloid differentiation/G0 arrest. Surveys of RA-induced gene expression from our and other laboratories revealed that CD38 is the earliest known receptor induced by RA. Crippling RA-induced CD38 expression cripples RA-induced differentiation, and ectopic over expression of CD38 enhances RA-induced differentiation. CD38 could potentially function through either ectoenzyme activity or receptor signaling to support differentiation: (1) The ectoenzyme activity catalyzes production of ADPR from NAD; and cADPR is able to mobilize calcium, a known regulator of differentiation and proliferation. (2) CD38 is also capable of dimerizing, which is another well known initiator of MAPK signaling. (3) CD38 has a cytosolic tail capable of binding to MAPK signaling molecules, in particular the c-Cbl adaptor. The proposed studies focus on the potential role of these functions in effecting the cellular outcome attributed to RA, namely differentiation and G0 cell cycle arrest. The proposed goals are to use small molecule probes that bind CD38, CD38 mutants, and X-ray crystallographic structures to characterize the mechanism by which CD38 promotes cell differentiation and arrest. The Specific Aims are to (1) determine the contribution of the CD38 ectoenzyme activity to RA-induced differentiation; (2) determine the contribution of receptor dimerization and the consequential cytosolic MAPK signaling complex; (3) determine the structure of the CD38-c-Cbl receptor-adaptor complex to elucidate the nature of the physical interfaces available for partners or intervention. In sum we intend to identify the CD38 activity needed to propel RA-induced differentiation. The Impact of these studies is a potential paradigm shift in understanding how RA works that will point to means of enhancing its mechanism of action. The Significance of the studies is that they could provide the basic mechanistic insight into a novel means of enhancing the chemopreventive, chemotherapeutic effects of RA. The Innovation is that a new paradigm based on receptor expression and signaling activities is proposed as a mechanism of action for RA in reverting neoplastic transformation. The basic Hypothesis is thus that RA-induces the early expression of CD38 which has different signal generating capabilities, and that these different capabilities could be exploited to enhance and control the differentiation/arrest program elicited by RA. The ultimate goal is to enhance the effects of RA.

描述（由申请人提供）：这是一项多位研究者的提案，旨在研究一种新方法，通过利用 RA 诱导的 CD38 受体表达和信号传导来增强视黄酸 (RA) 引起生长停滞和分化的机制。 RA 是一种癌症化学预防剂。它是饮食中提供的一种激素原，是一种常见的饮食不足。 RA可以将未成熟的肿瘤转化细胞转化为成熟的分化表型。拟议的研究利用未成熟的、未定型的人类白血病粒细胞-单核细胞前体细胞，当分别用 RA 或维生素 D3 (D3) 处理时，这些细胞会经历 G0 停滞以及骨髓或单核细胞分化。 RA 在诱导终末骨髓分化/G0 期停滞过程中引起 MAPK 信号激活。我们和其他实验室对 RA 诱导的基因表达的调查表明，CD38 是已知的最早由 RA 诱导的受体。削弱 RA 诱导的 CD38 表达会削弱 RA 诱导的分化，而 CD38 的异位过度表达会增强 RA 诱导的分化。 CD38 可能通过胞外酶活性或受体信号传导来支持分化：(1) 胞外酶活性催化 NAD 产生 ADPR； cADPR 能够调动钙，钙是一种已知的分化和增殖调节剂。 (2) CD38 还能够二聚化，这是另一个众所周知的 MAPK 信号传导启动子。 (3) CD38 具有能够结合 MAPK 信号分子，特别是 c-Cbl 接头的胞质尾部。拟议的研究重点关注这些功能在影响 RA 导致的细胞结果（即分化和 G0 细胞周期停滞）中的潜在作用。拟议的目标是使用结合 CD38、CD38 突变体和 X 射线晶体结构的小分子探针来表征 CD38 促进细胞分化和停滞的机制。具体目标是 (1) 确定 CD38 胞外酶活性对 RA 诱导分化的贡献； (2) 确定受体二聚化和随之而来的胞质 MAPK 信号复合物的贡献； (3)确定CD38-c-Cbl受体-适配器复合物的结构，以阐明可用于伴侣或干预的物理界面的性质。总之，我们打算确定推动 RA 诱导分化所需的 CD38 活性。这些研究的影响是理解 RA 工作原理的潜在范式转变，这将指出增强其作用机制的方法。这些研究的意义在于，它们可以为增强 RA 化学预防、化疗效果的新方法提供基本的机制见解。创新之处在于提出了一种基于受体表达和信号传导活动的新范例作为 RA 恢复肿瘤转化的作用机制。因此，基本假设是RA诱导CD38的早期表达，CD38具有不同的信号生成能力，并且可以利用这些不同的能力来增强和控制由RA引发的分化/阻滞程序。最终目标是增强 RA 的效果。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Potential for subsets of wt-NPM1 primary AML blasts to respond to retinoic acid treatment.

DOI：
10.18632/oncotarget.23642
发表时间：
2018-01-09
期刊：
Oncotarget
影响因子：
0
作者：
Bunaciu RP;MacDonald RJ;Gao F;Johnson LM;Varner JD;Wang X;Nataraj S;Guzman ML;Yen A
通讯作者：
Yen A

Dissecting the novel partners of nuclear c-Raf and its role in all-trans retinoic acid (ATRA)-induced myeloblastic leukemia cells differentiation.