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The Role of Zinc Finger Genes in Leukemogenesis

锌指基因在白血病发生中的作用

基本信息

批准号：
8490414
负责人：
Sinisa Dovat
金额：
$ 35.97万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490414
关键词：
Adolescent Adult Lymphoma Amino Acids Binding Biochemical Biological Biological Process CD8B1 gene Cell Cycle Progression Cell Cycle Regulation Cell Proliferation Cell physiology Cells Childhood Childhood Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia DNA Binding Data Development Down-Regulation Exhibits Functional disorder G1 Phase Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Hematopoietic Human Ikaros protein Immune In Vitro Infant Interleukin-2 Knockout Mice Lymphoma Malignant - descriptor Malignant Neoplasms Maps Molecular Mus Nucleic Acid Regulatory Sequences Patients Peripheral Phosphorylation Phosphorylation Site Phosphotransferases Process Protein Dephosphorylation Proteins RNA Interference RNA Splicing Regulation Regulatory Element Research Retroviral Vector Role S Phase Signal Transduction Signal Transduction Pathway Site Stem cells System T cell differentiation T-Cell Proliferation T-Lymphocyte Testing Transcriptional Regulation Transplantation Tumor Suppressor Proteins Up-Regulation Zinc Fingers adult leukemia bone marrow hyperplasia chromatin remodeling effective therapy in vivo insight leukemia leukemia/lymphoma leukemogenesis mouse model mutant novel overexpression promoter protein protein interaction reconstitution research study response thymocyte

项目摘要

PROJECT SUMMARY The objective of the proposed study is to understand the malignant transformation of hematopoietic cells by identifying the biological functions of Ikaros proteins. Ikaros is essential for hematopoietic development and acts as a tumor suppressor. The Ikaros gene is alternately spliced to generate multiple zinc finger proteins involved in gene regulation and chromatin remodeling. Our preliminary data show that: 1) Ikaros is phosphorylated at multiple evolutionarily conserved sites by CK2 and other kinases during G1 and S phase of the cell cycle 2) Phosphorylation of Ikaros at specific amino acids regulates its DNA-binding ability and subcellular localization. 3) Ikaros binds to the Bcl-xL gene promoter in vivo and disregulation of Ikaros activity is associated with upregulation of Bcl-xL gene expression. The specific aims of our proposals are: Specific Aim #1: To identify the specific phosphorylation sites responsible for Ikaros function in the regulation of transcription, cellular proliferation and differentiation. We hypothesize that phosphorylation of Ikaros interferes with its function in transcriptional regulation and chromatin remodeling and influences cellular proliferation. We will define phosphorylation sites that are critical for Ikaros function in DNA-binding, subcellular localization, and protein-protein interaction. The role of Ikaros phosphorylation in controlling cell cycle progression will be studied using a murine leukemia cellular system derived from Ikaros deficient mice. These cells will be transduced with wild type or Ikaros phosphomimetic mutants to define sites that are critical for Ikaros' function in cell cycle control. The role of Ikaros' phosphorylation in regulating T cell differentiation and T cell proliferation will be studied in vivo. Murine stem cells from mice with targeted disruption of Ikaros will be infected with retroviral vectors containing wild type Ikaros or phosphomimetic Ikaros mutants and transplanted into sublethally irradiated Ikaros knockout mice. The ability of phosphomimetic Ikaros mutants to restore normal T cell differentiation will be compared to that of wild type Ikaros. Specific aim #2: To dissect the mechanism by which Ikaros regulates Bcl-xL expression. Previous studies suggest that decreased Ikaros activity leads to overexpression of the Bcl-xL gene. We hypothesize that Ikaros exerts its tumor suppressor activity by negatively regulating Bcl-xL expression. To test this hypothesis we will determine whether increased Ikaros expression downregulates Bcl-xL transcription in human lymphoma cells and we will map the regions of the Bcl-xL upstream regulatory element (URE) that are critical for Ikaros-modulated control of Bcl-xL expression. These studies will provide the first detailed functional analysis of the signal transduction pathways that control the tumor suppressor function of Ikaros. Our research will provide new and important information on the mechanisms controlling the proliferation of hematopoietic cells and will yield insights into the pathophysiology and treatment of leukemia.

项目摘要这项研究的目的是了解造血细胞的恶性转化通过鉴定Ikaros蛋白的生物学功能。Ikaros对造血发育至关重要，作为肿瘤抑制剂。Ikaros基因交替剪接产生多个锌指蛋白参与基因调控和染色质重塑。我们的初步数据表明：1）Ikaros在多个进化保守位点被磷酸化，细胞周期G1期和S期的CK 2和其他激酶2）Ikaros在特定氨基酸的磷酸化酸调节其DNA结合能力和亚细胞定位。3)Ikaros与Bcl-xL基因启动子结合在体内，Ikaros活性的失调与Bcl-xL基因表达的上调有关。我们的建议的具体目标是：具体目标#1：确定特定的磷酸化位点负责Ikaros在调节转录、细胞增殖和分化中的功能。我们假设Ikaros磷酸化干扰其在转录调节中的功能，染色质重塑并影响细胞增殖。我们将定义磷酸化位点， Ikaros在DNA结合，亚细胞定位和蛋白质-蛋白质相互作用中的功能。Ikaros的角色将使用鼠白血病细胞系统研究磷酸化在控制细胞周期进程中的作用来源于Ikaros缺陷小鼠。这些细胞将用野生型或Ikaros磷酸化模拟物转导突变体，以确定对Ikaros在细胞周期控制中的功能至关重要的位点。伊卡洛斯的角色将在体内研究磷酸化在调节T细胞分化和T细胞增殖中的作用。鼠干来自具有Ikaros靶向破坏的小鼠的细胞将用含有野生型 Ikaros或拟磷酸化Ikaros突变体，并移植到亚致死辐射Ikaros敲除小鼠。将磷酸化模拟Ikaros突变体恢复正常T细胞分化的能力与磷酸化模拟Ikaros突变体恢复正常T细胞分化的能力进行比较。野生型伊卡洛斯具体目标#2：剖析Ikaros调节Bcl-xL表达的机制。先前的研究表明，Ikaros活性降低导致Bcl-xL基因的过表达。我们假设Ikaros通过负调节Bcl-xL表达发挥其肿瘤抑制活性。测试这一假设，我们将确定是否增加Ikaros表达下调Bcl-xL转录，我们将绘制Bcl-xL上游调控元件（URE）的区域，对于Ikaros调节的Bcl-xL表达的控制至关重要。这些研究将提供第一个详细的信号转导途径的功能分析，控制伊卡洛斯的肿瘤抑制功能我们的研究将提供新的重要信息，控制造血细胞增殖的机制，并将产生对病理生理学的见解和白血病的治疗。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Induction of senescence by adenosine suppressing the growth of lung cancer cells.

DOI：
10.1016/j.bbrc.2013.09.030
发表时间：
2013-10
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Dongqin Yang;Junyao Song;Lijun Wu;Yunfang Ma;Chunhua Song;S. Dovat;T. Nishizaki;Jie Liu
通讯作者：
Dongqin Yang;Junyao Song;Lijun Wu;Yunfang Ma;Chunhua Song;S. Dovat;T. Nishizaki;Jie Liu

Pathogenesis and regulation of cellular proliferation in acute lymphoblastic leukemia - the role of Ikaros.

急性淋巴细胞白血病的发病机制和细胞增殖调节 - Ikaros 的作用。

DOI：
发表时间：
2014
期刊：
Journal of B.U.ON. : official journal of the Balkan Union of Oncology
影响因子：
0
作者：
Wang,Haijun;Ouyang,Hongsheng;Lai,Liangxue;Petrovic-Dovat,Lidija;Stankov,Karmen;Bogdanovic,Gordana;Dovat,Sinisa
通讯作者：
Dovat,Sinisa

Ikaros, CK2 kinase, and the road to leukemia.

DOI：
10.1007/s11010-011-0964-5
发表时间：
2011-10
期刊：
MOLECULAR AND CELLULAR BIOCHEMISTRY
影响因子：
4.3
作者：
Dovat, Sinisa;Song, Chunhua;Payne, Kimberly J.;Li, Zhanjun
通讯作者：
Li, Zhanjun

AMID mediates adenosine-induced caspase-independent HuH-7 cell apoptosis.

AMID 介导腺苷诱导的不依赖 caspase 的 HuH-7 细胞凋亡。

DOI：
10.1159/000325203
发表时间：
2011
期刊：
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
影响因子：
0
作者：
Yang,Dongqin;Yaguchi,Takahiro;Nagata,Tetsu;Gotoh,Akinobu;Dovat,Sinisa;Song,Chunhua;Nishizaki,Tomoyuki
通讯作者：
Nishizaki,Tomoyuki

Ikaros in hematopoiesis and leukemia.