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The role of histone phosphorylation in arsenic-induced cell transformation and sk

组蛋白磷酸化在砷诱导的细胞转化和皮肤病中的作用

基本信息

批准号：
8019087
负责人：
Zigang Dong
金额：
$ 33.3万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8019087
关键词：
Address Adverse effects Agar Amino Acids Arsenic Biological Assay Carcinogens Cells Chemicals Chemoprevention Computer Simulation Computers Crystallography Databases Development Environmental Carcinogens Genes Goals Health Histone H2B Histone H3 Histones Human Hybrids In Vitro Kaempferols Knock-out Knockout Mice Knowledge Malignant Neoplasms Molecular Models Molecular and Cellular Biology Mus Mutation Names Phosphorylation Phosphorylation Site Phosphotransferases Play Point Mutation Preclinical Drug Evaluation Principal Investigator Process Protamine Kinase Research Role Screening procedure Skin Carcinogenesis Small Interfering RNA Structure Technology Testing base cancer chemoprevention carcinogenesis cell transformation design inhibitor/antagonist kaempferol mass spectrometer molecular modeling novel overexpression programs stable cell line ultraviolet upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Arsenic is a well-documented human carcinogen. Our goal is to address the central hypothesis that phosphorylation of histones and their upstream kinases play an important functional role in arsenic-induced cell transformation and carcinogenesis. Specific Aim 1 is to study the role of histone phosphorylation in arsenic-induced cell transformation; Specific Aim 2 is to investigate and identify the histone kinases that phosphorylate histone H3 and H2B at different amino acid residues; Specific Aim 3 is to study the crystal structure of histone kinase RSK2, perform in- silico screening and design RSK2 inhibitors for suppressing arsenic-induced histone phosphorylation and cell transformation; and Specific Aim 4 is to study the role of RSK2 in arsenic/ultraviolet A (UVA)-induced skin carcinogenesis and determine RSK2's potential as a target for chemoprevention of cancer. The strategy for Specific Aim 1 is to use point mutations at key phosphorylation sites of histone H3 and H2B siRNA gene knockdown and overexpressing stable cell lines to test the role of H3 and H2B in soft agar cell transformation assays. For Specific Aim 2, we will use in vitro kinase assays, specific mutations, LTQ Orbitrap hybrid mass spectrometer analysis and RSK2 knockout cells as well as inhibitors of RSK2. In Specific Aim 3, we will use x-ray crystallography to determine the structure of RSK2. Then we will use a super computer to screen a database of 2.5 million chemicals to find inhibitors for RSK2 to be tested in an in vitro kinase assay. In Specific Aim 4, we will test the effect of the RSK2 inhibitor kaempferol and RSK2 knockout mice in UVA/arsenic-induced mouse skin carcinogenesis. Such knowledge will facilitate the design of more effective and specific strategies with fewer side effects for chemoprevention of arsenic- induced cancer. PUBLIC HEALTH RELEVANCE: Environmental arsenic contamination is a major problem in many parts of the world and is a well-documented human carcinogen. By using state-of-the-art technology such as x-ray crystallography, super computer based molecular modeling and drug screen, cellular and molecular biology and gene knockout mice, we will study the novel mechanism involved in histone phosphorylation on arsenic-induced cell transformation to cancer and the carcinogenesis process. These studies will facilitate the development of more effective agents with fewer side effects for chemoprevention against environmental carcinogens such as arsenic- induced cancer.

描述（由申请人提供）：