REGULATION OF CADMIUM INDUCIBLE GENE EXPRESSION

镉诱导基因表达的调控

• 批准号: 6178465
• 负责人: JONATHAN H FREEDMAN
• 金额: $ 19.38万
• 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/6178465
• 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：（改编自研究者摘要）培养的 细胞和动物的镉诱导表达干部的防御， 修复蛋白，以及原癌基因，中间代谢酶 和结构蛋白质。镉影响表达的机制 这些基因中的大多数仍然是未知的。镉已被证明会影响信号 由蛋白激酶A、蛋白激酶C和 钙调素我们认为，镉影响这些途径，以影响 多个基因的转录，这些途径的激活可能 可能是镉引起的疾病、细胞凋亡和癌症的原因。我们将 研究镉诱导基因转录的假设， 激活小杆线虫中信号转导级联的能力 优雅的。本研究的目的是（a）分离C.线虫基因， 蒸腾作用是由镉和调节信号的物质引起的 转导级联（例如，钙，佛波酯，cAMP），然后 表征响应于这些试剂的细胞表达模式; (b)确定这些启动子中的上游调控元件（URES） 介导镉诱导和细胞特异性模式的基因 （c）确定镉响应性URES是否也介导 通过信号转导级联转录;和（d）鉴定 C.在人肝来源的细胞系中的线虫镉响应性mRNA，和 确定它们的表达是否通过金属和第二信使调节。 鉴定其转录受镉和锌影响的基因。 第二信使会暗示金属是通过一个信号 转导途径。细胞和发育阶段特异性的常见模式 暴露于镉和第二信使后的表达将进一步 表明了共同的调节途径。最后，识别单个 同时赋予金属和第二信使反应的URE将证实 镉是通过信号传导级联发挥作用的我们觉得 从建议的C. elegans研究将适用于 了解镉如何影响人类健康， 信号转导途径和调节的进化保守性 控制基因转录的机制。