The transcriptional basis of tumor promotion

肿瘤促进的转录基础

• 批准号: 6944200
• 负责人: JOSEPH D LOCKER
• 金额: $ 34.18万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944200
• 关键词: apoptosis; biological signal transduction; carcinogens; cell cycle; cell growth regulation; cell proliferation; drug /agent; gene expression; gene targeting; genetic regulation; genetic transcription; genetically modified animals; hyperplasia; laboratory mouse; laboratory rat; liver cells; liver pharmacology; liver regeneration; microarray technology; mitogens; neoplastic process; nuclear receptors; pyridine; regulatory gene; tissue /cell culture; tumor promoters

DESCRIPTION (provided by applicant): Partial hepatectomy induces liver regeneration while a number of drugs and hormones induce liver hyperplasia. Both are proliferative responses that promote cancer, but our research has demonstrated that the two responses are independent and initiated by different transcriptional signals. The drug TCPOBOP induces hyperplasia and is also a strong tumor promoter in mice. TCPOBOP is a ligand for the xenobiotic nuclear receptor CAR, which directly activates an immediate-early transcriptional response. Thyroid hormone (T3) binds to a similar nuclear receptor (TR), and both CAR and TR activate very similar response elements in genes. T3 induces hyperplasia in rat liver, but surprisingly, instead of promoting, it suppresses carcinogenesis. We propose that liver regeneration and both hyperplastic agents act through different transcriptional signals that converge on a common set of target genes that lead to proliferation. Each treatment also acts on a unique set of genes that makes the responses different. The effects will be resolved through complementary experimental approaches. Microarray analysis (Aim 1) will determine the common and distinctive patterns of gene regulation that lead to proliferation. Transcriptional studies (Aim 2) will focus on early response genes common to both regeneration and hyperplasia. Experiments will work out novel transcriptional mechanisms for CAR and resolve how the TR and CAR can discriminate regulatory sites. Proliferation and apoptosis (Aim 3) will be studied in both cell culture and knockout animals, to learn how proliferation is controlled, whether hyperplasia protects against apoptosis, and the degree of independence between the two proliferation pathways.

描述（由申请人提供）：部分肝切除术诱导肝再生，而许多药物和激素诱导肝增生。两者都是促进癌症的增殖反应，但我们的研究表明，这两种反应是独立的，由不同的转录信号启动。药物TCPOBOP诱导增生，也是小鼠中的强肿瘤促进剂。TCPOBOP是异生物质核受体CAR的配体，其直接激活立即早期转录反应。甲状腺激素（T3）与类似的核受体（TR）结合，CAR和TR激活基因中非常相似的反应元件。T3诱导大鼠肝脏增生，但令人惊讶的是，它不是促进，而是抑制致癌作用。我们认为肝再生和两种增生因子通过不同的转录信号作用，这些信号聚集在一组共同的导致增殖的靶基因上。每种治疗方法也作用于一组独特的基因，使反应不同。这些影响将通过补充实验方法解决。微阵列分析（目标1）将确定导致增殖的基因调控的共同和独特模式。转录研究（目标2）将集中在再生和增生共同的早期反应基因。实验将研究CAR的新的转录机制，并解决TR和CAR如何区分调控位点。将在细胞培养和基因敲除动物中研究增殖和凋亡（目的3），以了解增殖是如何控制的，增生是否保护细胞凋亡，以及两种增殖途径之间的独立程度。