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The Role of Zinc Finger Genes in Leukemogenesis

The Role of Zinc Finger Genes in Leukemogenesis
锌指基因在白血病发生中的作用
批准号:
8490414
负责人:
Sinisa Dovat
金额:
$35.97万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-07-01 至 2015-06-30

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中文摘要
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英文摘要
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.
期刊论文(16)
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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: --
作者: [Wang,Haijun, Ouyang,Hongsheng, Lai,Liangxue, Petrovic-Dovat,Lidija, Stankov,Karmen, Bogdanovic,Gordana, Dovat,Sinisa]
通讯作者: Dovat,Sinisa
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: --
作者: [Yang,Dongqin, Yaguchi,Takahiro, Nagata,Tetsu, Gotoh,Akinobu, Dovat,Sinisa, Song,Chunhua, Nishizaki,Tomoyuki]
通讯作者: Nishizaki,Tomoyuki
10
    Novel targeted therapy to reduce health disparities in pediatric leukemia
    Targeting CK2 oncogenic pathway to overcome drug resistance in high-risk leukemia
    Targeting CRLF2 and Ikaros Alterations to Reduce Health Disparities in Childhood Leukemia
    • 批准号:
      9302326
    • 项目类别:
    • 资助金额:
      $36.05万
    • 财政年份:
      2016
    • 负责人:
      Sinisa Dovat
    • 依托单位:
    Targeting CRLF2 and Ikaros Alterations to Reduce Health Disparities in Childhood Leukemia
    • 批准号:
      9753178
    • 项目类别:
    • 资助金额:
      $34.97万
    • 财政年份:
      2016
    • 负责人:
      Sinisa Dovat
    • 依托单位:
    海外基金