The Role of Zinc Finger Genes in Cellular Proliferation

锌指基因在细胞增殖中的作用

• 批准号: 6966801
• 负责人: Sinisa Dovat
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-12 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966801
• 关键词: 3T3 cells; DNA binding protein; aminoacid; cell differentiation; cell growth regulation; cell proliferation; clinical research; cytogenetics; flow cytometry; gene expression; gene induction /repression; genetic regulation; genetically modified animals; hematopoiesis; human tissue; laboratory mouse; molecular genetics; neoplastic transformation; phosphoproteins; phosphorylation; protein kinase; protein structure; thin layer chromatography; transfection

DESCRIPTION (provided by applicant): The objective of the present study is to understand the normal hematopoiesis and malignant transformation of hematopoietic cells by studying biological functions of two genes, Ikaros and Helios. Ikaros encodes a zinc finger protein involved in heritable gene silencing. Gene disruption experiments have shown that expression of Ikaros is necessary for the development of both B and T cells and suggested that Ikaros can act as a tumor suppressor. Helios encodes a protein that is structurally similar to Ikaros and is only expressed in T cells. The biological function of Helios is unknown. The aims of this proposal are: Research Aim #1: Study the molecular mechanisms by which Ikaros affects cellular proliferation and differentiation. We will identify the constitutively phosphorylated amino acids in this protein. Phosphomimetic experiments will be performed to study how the phosphorylation status of particular amino acid(s) affects Ikaros function. We will study how overexpressing particular phosphomimetic Ikaros mutants affects cellular proliferation. Research Aim #2: Determine the functional significance of the phosphorylation of Ikaros protein at an evolutionarily conserved linker sequence. We will try to identify the kinase that phosphorylates this conserved linker and study the pathway involved. Research Aim #3: Determine the role of Helios in human malignancies. Our preliminary data suggest that expression of Helios in B cells contributes to malignant transformation in mouse and human. The molecular mechanism of how Helios promotes malignant transformation will be studied. We will establish the incidence and significance of Helios expression in human malignancies and determine the molecular mechanisms by which Helios affects B cell development in humans. These studies will provide important information on the mechanisms controlling development and proliferation of hematopoietic cells and will yield insights into the pathophysiology and treatment of leukemia.

描述（由申请人提供）：本研究的目的是通过研究Ikaros和Helios两个基因的生物学功能来了解造血细胞的正常造血和恶性转化。Ikaros编码一种锌指蛋白，这种蛋白与遗传性基因沉默有关。基因破坏实验表明，Ikaros的表达对于B细胞和T细胞的发育都是必要的，并提示Ikaros可以作为肿瘤抑制因子。Helios编码的一种蛋白质在结构上与Ikaros相似，只在T细胞中表达。太阳神的生物学功能尚不清楚。