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两个基因的生物学功能，Ikaros和Helios的生物学功能来了解造血细胞的正常造血和恶性转化。 Ikaros编码参与基因沉默的锌指蛋白。基因破坏实验表明，Ikaros的表达对于B和T细胞的发展是必要的，并建议Ikaros可以充当肿瘤抑制器。 Helios编码一种与Ikaros结构相似的蛋白质，仅在T细胞中表达。 Helios的生物学功能尚不清楚。 该提案的目的是：研究目的＃1：研究iKaros影响细胞增殖和分化的分子机制。我们将在该蛋白质中鉴定组成型磷酸化的氨基酸。将进行磷酸化实验，以研究特定氨基酸的磷酸化状态如何影响Ikaros功能。我们将研究过表达特定的磷酸化Ikaros突变体如何影响细胞增殖。研究目的＃2：确定Ikaros蛋白在进化保守的接头序列上的磷酸化的功能意义。我们将尝试确定磷酸化该保守接头并研究所涉及的途径的激酶。研究目的＃3：确定Helios在人类恶性肿瘤中的作用。我们的初步数据表明，B细胞中HELIOS的表达有助于小鼠和人类的恶性转化。将研究Helios如何促进恶性转化的分子机制。我们将确定Helios表达在人类恶性肿瘤中的发病率和意义，并确定Helios影响人类B细胞发育的分子机制。这些研究将提供有关控制造血细胞发育和增殖的机制的重要信息，并将对白血病的病理生理学和治疗产生见解。