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Selenium molecular signaling in human prostate cancer

人类前列腺癌中的硒分子信号传导

基本信息

批准号：
7229574
负责人：
CLEMENT C IP
金额：
$ 36.62万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229574
关键词：
Address Age-Years Androgens Apoptosis Awareness Biological Markers Biopsy CCAAT-Enhancer-Binding Proteins Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cells Chemoprevention Chemopreventive Agent Clinical Management Cyclin-Dependent Kinases Cyclins DNA Binding DNA biosynthesis DNA chemical synthesis Depressed mood Dimerization Double-Blind Method Event Exposure to Flow Cytometry Future Gene Expression Genes Genetic Transcription Goals Growth Hour Incidence Knowledge LNCaP Length Malignant neoplasm of prostate Mediating Mitosis Molecular Numbers PC3 cell line Participant Pharmaceutical Preparations Phase Phase Transition Physiological Placebo Control Plasma Cells Play Prostate Protein Family Proteins Protocols documentation Randomized Regulator Genes Research Role Sampling Selenium Selenium/vitamin E Signal Transduction Time Tissues Transcript Transcriptional Regulation Up-Regulation activating transcription factor base cancer cell cancer chemoprevention design drug carcinogenesis inhibitor/antagonist interest men repository transcription factor

项目摘要

DESCRIPTION (provided by applicant): Scanty information is currently available on the molecular mechanism of selenium chemoprevention in prostate cancer. Preliminary studies showed that physiological concentrations of a selenium metabolite inhibited the growth of both the androgen-responsive LNCaP and the androgen-nonresponsive PC-3 human prostate cancer cells. Analysis by flow cytometry indicated that selenium blocked cell cycle progression at multiple transition points after 24 hours and induced apoptosis after 48 hours. The Affymetrix GeneChip was used to profile the gene expression changes that might mediate these cellular events. Immediately before growth inhibition became evident in selenium-treated cells, a number of cyclins and CDKs were found to be depressed. These changes were accompanied by an increased expression of CDK inhibitors and other regulatory molecules that are known to reduce the activation of CDKs. Additionally, selenium also decreased the expression of genes involved in S phase transition, DNA synthesis and mitosis. Alterations in the transcript signal of many of these genes were confirmed at the protein level. Of particular interest is GADD153, a gene well documented to play an essential role in cell cycle control and apoptosis. The reasons for focusing on GADD153 are (a) it is one of the most highly modulated genes by selenium; (b) the induction occurs early and persists following selenium exposure; (c) as a transcription factor and a dimerization partner to other C/EBP and ATF family of proteins, it is an upstream target and is likely to modulate the transcription of many genes; and (d) the increase of GADD153 is observed in 4 different prostate cancer cell lines. The goal of this project is to investigate the role of GADD153 in contributing to the molecular effects of selenium. The research plan consists of 4 aims. Aim 1 is to determine the DNA binding activity of GADD153 in selenium-treated cells, and to identify the genes modulated directly by GADD153. Aim 2 is to characterize the dimerization partners of GADD153 following exposure to selenium. Aim 3 is to evaluate the changes in cellular responsiveness to selenium in the presence of antisense GADD153. Aim 4 is to study the transcriptional control of GADD153 by selenium. The proposed research is thus designed to examine systemically the impact of GADD153 induction as a result of selenium treatment.

描述（由申请人提供）：目前关于硒化学预防前列腺癌的分子机制的信息很少。初步研究表明，生理浓度的硒代谢物抑制雄激素反应性LNCaP和雄激素非反应性PC-3人前列腺癌细胞的生长。流式细胞仪分析表明，硒在24小时后在多个转换点阻断细胞周期进程，并在48小时后诱导凋亡。使用Affyssin基因芯片来分析可能介导这些细胞事件的基因表达变化。在硒处理的细胞中生长抑制变得明显之前，发现一些细胞周期蛋白和CDK被抑制。这些变化伴随着CDK抑制剂和其他已知可降低CDK活化的调节分子表达的增加。此外，硒还降低了参与S期转变、DNA合成和有丝分裂的基因的表达。在蛋白质水平上证实了许多这些基因的转录信号的改变。特别令人感兴趣的是GADD 153，这是一种在细胞周期控制和凋亡中发挥重要作用的基因。关注GADD 153的原因是：（a）它是受硒调节最高的基因之一;（b）诱导发生得早，并在硒暴露后持续存在;（B）作为转录因子和其他C/EBP和ATF蛋白家族的二聚化伴侣，它是上游靶点，可能调节许多基因的转录;和（d）在4种不同的前列腺癌细胞系中观察到GADD 153的增加。本项目的目标是研究GADD 153在硒分子效应中的作用。研究计划包括四个目标。目的1：检测硒处理细胞中GADD 153的DNA结合活性，并鉴定GADD 153直接调控的基因。目的2是表征暴露于硒后GADD 153的二聚化伴侣。目的3：研究反义GADD 153对硒诱导的细胞反应性的影响。目的4研究硒对GADD 153基因的转录调控。因此，拟议的研究旨在系统地检查硒处理对GADD 153诱导的影响。