Survival Signaling After Genotoxic Insult

基因毒性侮辱后的生存信号

基本信息

批准号：
7324802
负责人：
SUSAN M CERYAK
金额：
$ 23.79万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7324802
关键词：
Address Alleles Apoptosis Apoptotic BAD gene Bad protein Biological Biological Assay Biological Markers Biological Models Bypass Carcinogens Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Progression Cell Death Cell Proliferation Cell Survival Cells Cessation of life Chemicals Chromosomes Complex Condition Cyclins DNA Adduction DNA Adducts DNA Damage DNA biosynthesis DNA chemical synthesis Data Diploidy Dominant-Negative Mutation Drug Design Early Diagnosis Environmental and Occupational Exposure Equilibrium Event Evolution Exposure to Face Fibroblasts Foundations Frequencies G2/M Checkpoint Pathway Gene Activation Gene Proteins Gene Silencing Genes Genetic Genomic Instability Genotoxic Stress Growth Human In Situ Incidence Injury Kinetics Lead Lesion Litigation Lung Maintenance Malignant Neoplasms Mediating Methods Mitotic Molecular Molecular Target Mutagenesis Mutagens Mutation Neoplastic Cell Transformation Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiological Play Population Post-Translational Protein Processing Protein Tyrosine Kinase Protein Tyrosine Phosphatase Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Public Health Range Regulation Resistance Risk Factors Role S-Phase Fraction Signal Pathway Signal Transduction Small Interfering RNA Source Survivors TP53 gene Telomerase Testing Thinking Tyrosine Phosphorylation Up-Regulation base cancer therapy carcinogenesis cell growth chromium hexavalent ion exposed human population genotoxicity human large airway epithelial cell indexing inhibitor/antagonist insight lung carcinogenesis neoplastic programs protein expression resistance mechanism respiratory response tool tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Inappropriate activation/inactivation of key signals that control cell survival after genotoxic insult can contribute to autonomous growth and neoplastic transformation. An initial consequence of genotoxic injury is cell cycle checkpoint arrest but genotoxicity may also activate cell death pathways of apoptosis or terminal growth arrest. Cellular survival responses to genotoxic insult may produce intrinsic death-resistance; such a selective growth advantage may allow for emergence of a transformed phenotype. Certain forms of hexavalent chromium [(Cr(VI)] are known human respiratory carcinogens that can be employed as useful genotoxic tools with relevant toxicological importance. Our preliminary studies suggest that maintenance of protein tyrosine phosphorylation, which is coincident with AKT activation, overrides Cr-induced growth arrest and enhances clonogenic survival. Constitutive AKT activation is known to play an important role in carcinogenesis. Therefore, the overall objective of this proposal is to elucidate the coordinate signaling events that mediate cell fate determination and survival after genotoxic insult. The dual overarching hypotheses of the proposed studies are that: 1) AKT activation shifts the balance of cell fates, toward survival, after Cr(Vl) genotoxic insult; and 2) AKT activation in the face of Cr(Vl) genotoxic insult increases genomic instability. To test these hypotheses, we will employ molecular, pharmacological and genetic approaches, by using relevant model systems of human diploid lung fibroblasts (HLF), and human large airway epithelial cells (HLAE) and studying the involvement of key signaling components of the AKT pathway. The molecular circuitry of the AKT effect will be delineated in Aim 1, and the consequences of an AKT-induced "override" of the genotoxin-elicited program of cell death will be investigated in Aim 2. Aim 3 will identify the role of AKT in resistance to Cr(Vl)-induced clonogenic lethality in a subclonal population of cells with acquired resistance to Cr-induced clonogenic death. We will use soluble Na2CrO4 at a range of concentrations relevant to human exposure, and for which the DNA adduct frequencies and genotoxic lesions are well documented. Results of the proposed studies will identify molecular mechanism(s) that confer a growth advantage to cells after genotoxic insult, and add new insights to the understanding of Cr(Vl)-induced lung carcinogenesis, while addressing a need for sensitive and specific molecular indices that can be correlated with exposure to carcinogenic agents, as well as with their cancer incidence. Delineation of the molecular circuitry involved in AKT survival signaling may have the added benefit of identifying molecular targets for rational drug design in anti-cancer therapy.

描述（由申请人提供）：基因毒性损伤后控制细胞存活的关键信号的不适当激活/失活可能有助于自主生长和肿瘤转化。基因毒性损伤的最初后果是细胞周期检查点停滞，但基因毒性也可能激活细胞凋亡或终末生长停滞的细胞死亡途径。细胞对基因毒性损伤的生存反应可能会产生内在的死亡抵抗力；这种选择性生长优势可能会导致转化表型的出现。某些形式的六价铬 [(Cr(VI)] 是已知的人类呼吸道致癌物，可用作具有相关毒理学重要性的有用基因毒性工具。我们的初步研究表明，与 AKT 激活同时发生的蛋白质酪氨酸磷酸化的维持会覆盖 Cr已知 AKT 诱导的生长停滞和增强克隆存活在癌发生中发挥重要作用。协调介导细胞命运决定和基因毒性损伤后存活的信号事件所提出的研究的双重总体假设是：1) AKT 激活在 Cr(VI) 基因毒性损伤后改变细胞命运的平衡，转向存活； 2) 面对 Cr(VI) 基因毒性损伤时 AKT 激活会增加基因组不稳定性。为了检验这些假设，我们将采用分子、药理学和遗传学方法，通过使用人二倍体肺成纤维细胞（HLF）和人大气道上皮细胞（HLAE）的相关模型系统，并研究 AKT 通路关键信号成分的参与。目标 1 将描述 AKT 效应的分子回路，目标 2 将研究 AKT 诱导“覆盖”基因毒素引起的细胞死亡程序的后果。目标 3 将确定 AKT 在对 Cr(VI) 诱导的克隆致死性具有抗性的细胞亚克隆群体中具有对 Cr(VI) 诱导的克隆致死的获得性抗性。我们将使用与人体暴露相关的一系列浓度的可溶性 Na2CrO4，并且其 DNA 加合物频率和基因毒性损伤都有详细记录。拟议研究的结果将确定在基因毒性损伤后赋予细胞生长优势的分子机制，并为理解 Cr(VI) 诱导的肺癌发生提供新的见解，同时解决对敏感和特定分子指数的需求这可能与接触致癌物质及其癌症发病率有关。描绘 AKT 生存信号传导所涉及的分子电路可能具有额外的好处，可以识别抗癌治疗中合理药物设计的分子靶标。