The transcriptional basis of tumor promotion

肿瘤促进的转录基础

• 批准号: 7247263
• 负责人: JOSEPH D LOCKER
• 金额: $ 32.41万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247263
• 关键词: Animal Model; Apoptosis; Binding; Carcinogens; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell Survival; Cells; Complement; Cultured Cells; ERG gene; Equilibrium; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Hepatocyte; Hormone Responsive; Hormones; Hyperplasia; Induced Mutation; Injury; Knockout Mice; Lead; Learning; Ligands; Liver; Liver Regeneration; Liver diseases; Malignant Neoplasms; Microarray Analysis; Mitogens; Mus; Natural regeneration; Nuclear Receptors; Numbers; Partial Hepatectomy; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Pituitary Gland; Proliferating; Rattus; Regulation; Research; Resources; Response Elements; Signal Transduction; Site; Stimulus; Transcriptional Regulation; Triiodothyronine; Tumor Promoters; Tumor Promotion; Work; Xenobiotics; base; carcinogenesis; knockout animal; liver cell proliferation; liver hyperplasia; novel; research study; response; transcription factor

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(申请人提供)：部分肝切除可诱导肝脏再生，而一些药物和激素可诱导肝脏增生。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在小鼠体内诱导增殖，也是一种强烈的肿瘤促进剂。TCPOBOP是异源核受体CAR的配体，它直接激活即刻-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都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，它非但没有促进，反而抑制了癌变。我们认为，肝再生和两种增生剂都通过不同的转录信号发挥作用，这些转录信号聚集在一组共同的靶基因上，导致增殖。每种治疗方法还作用于一组独特的基因，使反应不同。这些影响将通过互补的实验方法来解决。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)将集中在再生和增殖共同的早期反应基因上。实验将为CAR找出新的转录机制，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(目标3)，以了解如何控制增殖，增殖是否保护细胞免于凋亡，以及这两条增殖途径之间的独立程度。