REGULATION OF CADMIUM INDUCIBLE GENE EXPRESSION

镉诱导基因表达的调控

• 批准号: 6525298
• 负责人: JONATHAN H FREEDMAN
• 金额: $ 19.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525298
• 关键词: Caenorhabditis elegans; biological signal transduction; cadmium; calcium flux; cell line; cyclic AMP; gene expression; genetic mapping; genetic promoter element; genetic regulation; genetic transcription; human tissue; messenger RNA; phorbols; second messengers; tissue /cell culture

DESCRIPTION: (Adapted from the Investigator's Abstract) Exposure of cultured cells and animals to cadmium induces the expression of a cadre of defense and repair proteins, as well as proto-oncogenes, intermediate metabolism enzymes and structural proteins. The mechanism by which cadmium affects the expression of most of these genes remains unknown. Cadmium has been shown to affect signal transduction pathways regulated by protein kinase A, protein kinase C and calmodulin. We propose that cadmium influences these pathways to affect the transcription of multiple genes and that the activation of these pathways may be a cause of cadmium-induced diseases, apoptosis, and cancer. We will investigate the hypothesis that cadmium induces gene transcription due to its ability to activate signal transduction cascades in the nematode Caenorhabditis elegans. The goals of this research are to (a) isolate C. elegans genes whose transpiration is induced both by cadmium and agents that modulate signal transduction cascades (e.g., calcium, phorbol esters, cAMP) and then characterize the cellular patterns of expression in response to these agents; (b) identify upstream regulatory elements (UREs) in the promoters of these genes that mediate cadmium-inducibility and cell-specific patterns of transcription; (c) determine if the cadmium-responsive UREs also mediate transcription via signal transduction cascades; and (d) identify homologues of C. elegans cadmium-responsive mRNAs in a human liver-derived cell line, and determine if their expression is regulated via metals and second messengers. Identification of genes whose transcription is affected by both cadmium and second messengers would suggest that the metal is acting via a signal transduction pathway. Common patterns of cell- and developmental stage-specific expression following exposure to cadmium and second messengers would further indicate common pathways of regulation. Finally, the identification of a single URE that confers both metal and second messenger responsiveness would confirm that cadmium is functioning through a signal transduction cascade. We feel that the information derived from the proposed C. elegans studies will be applicable to understanding how cadmium influences human health because of the evolutionarily conserved nature of signal transduction pathways and regulatory mechanisms controlling gene transcription.

描述：(改编自调查人员摘要)暴露培养的 细胞和动物对镉诱导表达的一种防御和 修复蛋白、原癌基因、中间代谢酶 和结构蛋白。镉影响基因表达的机制 这些基因中的大多数还不清楚。镉已被证明会影响信号 蛋白激酶A、蛋白激酶C和蛋白激酶C调控的信号传导通路 钙调素。我们认为，镉影响这些途径，从而影响 多个基因的转录，这些通路的激活可能 是镉引起的疾病、细胞凋亡和癌症的原因之一。我们会 研究镉诱导基因转录的假设是由于它的 线虫激活信号转导通路的能力 优雅女装。这项研究的目标是(A)分离线虫的基因 蒸腾作用是由镉和信号调节剂诱导的 转导级联(如钙、佛波酯、cAMP)，然后 描述细胞对这些药物的反应模式； (B)确定这些项目的发起人中的上游监管要素 介导镉诱导的基因和细胞特异性模式 转录；(C)确定镉反应蛋白是否也参与 通过信号转导级联转录；和(D)确定 人肝来源细胞系中线虫对镉反应的mRNAs，以及 确定它们的表达是否通过金属和第二信使调节。 Cd和Cd共同影响转录的基因鉴定 第二个信使会暗示金属是通过一个信号起作用的 转导途径。细胞和发育阶段特有的常见模式 接触镉和第二信使后的表达会进一步 指出监管的共同路径。最后，确定了一个单一的 同时赋予金属和第二信使响应性的URE将证实 镉是通过一系列信号转导起作用的。我们觉得 从拟议的线虫研究中获得的信息将适用 了解镉是如何影响人类健康的 信号转导通路和调控的进化保守性 控制基因转录的机制。