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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：
8215643
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215643
关键词：
Address Adverse effects Agar Amino Acids Arsenic Biological Assay Carcinogens Cells Chemicals Chemoprevention Chemopreventive Agent Computer Simulation Computers Crystallography Databases Development Environmental Carcinogens Genes Goals Histone H2B Histone H3 Histones Human Hybrids In Vitro Kaempferols Knock-out Knockout Mice Knowledge Malignant Neoplasms Molecular Molecular Models Molecular and Cellular Biology Mus Mutation Phosphorylation Phosphorylation Site Phosphotransferases Play Point Mutation Preclinical Drug Evaluation Process Protamine Kinase Protein Kinase Role Screening procedure Skin Cancer Skin Carcinogenesis Small Interfering RNA Structure Technology Testing Tumor Promotion Work base cancer chemoprevention cancer prevention carcinogenesis cell transformation design inhibitor/antagonist kaempferol mass spectrometer molecular modeling novel overexpression 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.

描述（由申请人提供）：砷是一种有据可查的人类致癌物质。我们的目标是要解决的核心假设，磷酸化组蛋白及其上游激酶在砷诱导的细胞转化和癌变中发挥重要的功能作用。具体目标1是研究组蛋白磷酸化在砷诱导的细胞转化中的作用，具体目标2是研究和鉴定磷酸化组蛋白H3和H2 B不同氨基酸残基的组蛋白激酶;具体目标3是研究组蛋白激酶RSK 2的晶体结构，进行计算机筛选并设计RSK 2抑制剂，用于抑制砷诱导的组蛋白磷酸化和细胞转化;具体目标4是研究RSK 2在砷/紫外线A（UVA）诱导的皮肤癌发生中的作用，并确定RSK 2作为癌症化学预防靶点的潜力。特定目标1的策略是在组蛋白H3和H2 B siRNA基因敲低的关键磷酸化位点使用点突变，并过表达稳定细胞系，以测试H3和H2 B在软琼脂细胞转化试验中的作用。对于特异性目标2，我们将使用体外激酶测定、特异性突变、LTQ Orbitrap混合质谱仪分析和RSK 2敲除细胞以及RSK 2抑制剂。在具体目标3中，我们将使用X射线晶体学来确定RSK 2的结构。然后，我们将使用超级计算机筛选250万种化学物质的数据库，以找到RSK 2的抑制剂，并在体外激酶试验中进行测试。在具体目标4中，我们将测试RSK 2抑制剂山奈酚和RSK 2基因敲除小鼠在UVA/砷诱导的小鼠皮肤癌发生中的作用。这些知识将有助于设计更有效和更具体的策略，减少副作用，用于砷诱导的癌症的化学预防。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（3）

UVB-induced COX-2 expression requires histone H3 phosphorylation at Ser10 and Ser28.

DOI：
10.1038/onc.2012.71
发表时间：
2013-01-24
期刊：
ONCOGENE
影响因子：
8
作者：
Keum, Y-S;Kim, H-G;Bode, A. M.;Surh, Y-J;Dong, Z.
通讯作者：
Dong, Z.

Prediction of molecular targets of cancer preventing flavonoid compounds using computational methods.

DOI：
10.1371/journal.pone.0038261
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Chen H;Yao K;Nadas J;Bode AM;Malakhova M;Oi N;Li H;Lubet RA;Dong Z
通讯作者：
Dong Z

Identification of an Aurora kinase inhibitor specific for the Aurora B isoform.

鉴定具有极光B同工型特异性的Aurora激酶抑制剂。

DOI：
10.1158/0008-5472.can-12-2784
发表时间：
2013-01-15
期刊：
Cancer research
影响因子：
11.2
作者：
Xie H;Lee MH;Zhu F;Reddy K;Peng C;Li Y;Lim DY;Kim DJ;Li X;Kang S;Li H;Ma W;Lubet RA;Ding J;Bode AM;Dong Z
通讯作者：
Dong Z

6-C-(E-phenylethenyl)-naringenin suppresses colorectal cancer growth by inhibiting cyclooxygenase-1.