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

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：
8296355
负责人：
Sinisa Dovat
金额：
$ 37.79万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8296355
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.

项目总结