The transcriptional basis of tumor promotion

肿瘤促进的转录基础

• 批准号: 8061686
• 负责人: JOSEPH D LOCKER
• 金额: $ 35.49万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061686
• 关键词: Address; Adenoviruses; Apoptosis; Binding; Binding Sites; Biological; Biological Process; Cell Cycle; Cell Proliferation; Complex; Cyclin D1; Funding; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Health; Hepatocyte; Hormones; Hyperplasia; Individual; Injury; Investigation; Knockout Mice; Lead; Ligands; Liver; Liver Regeneration; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Mitogens; Modeling; Molecular; Molecular Profiling; Mus; Mutate; Natural regeneration; Nuclear Receptors; Nucleic Acid Regulatory Sequences; Partial Hepatectomy; Pathway interactions; Pharmaceutical Preparations; Phase; Process; Proteins; RXR; Rattus; Regulation; Regulatory Pathway; Research; Research Personnel; Response Elements; Role; Stimulus; System; Tertiary Protein Structure; Testing; Thyroid Hormones; Transcription Coactivator; Transcription Factor AP-1; Transcriptional Activation; Transcriptional Regulation; Tumor Promoters; Tumor Promotion; Work; activating transcription factor; base; cell growth; cell type; chromatin remodeling; novel; null mutation; rapid growth; reconstitution; research study; response; transcription factor

DESCRIPTION (provided by applicant): We compared four processes that activate cell proliferation in the liver: (1) hyperplasia induced by the tumor promoter, TCPOBOP; (2) antipromotional hyperplasia induced by thyroid hormone; (3) rapid liver regeneration after partial hepatectomy (PH) in the rat; and (4) more protracted regeneration after PH in the mouse. The first phase of the project generated a comprehensive system of microarray expression profiles of all four processes. TCPOBOP is a direct ligand for the nuclear receptor transcription factor, CAR, and rapidly induces liver growth and cell proliferation. The expression profiles showed rapid induction of Gadd45¿, Jun, and Fosl2 mRNA after TCPOBOP treatment; we focused on transcriptional regulation of these three genes, and on Cyclin D1 as their downstream target. A Gadd45¿-null mouse had active proliferation after TCPOBOP treatment, but impaired transcription and liver growth. Molecular studies showed that Gadd45¿ directly binds CAR and acts as a transcriptional coactivator. Thus, rapid induction of Gadd45¿ is anabolic and enables the high rate of transcription needed for rapid growth. However, other investigators have found that Gadd45¿ regulates apoptosis and proliferation. The research proposed in Aim 1 will investigate how Gadd45¿, only 18 kD, can function as a coactivator, by determining its binding partners in the transcription complex, and its effects on progressive chromatin remodeling during transcriptional activation. Other experiments will determine how Gadd45¿ can have so many critical functions, by mutating individual protein domains and testing each for effects on CAR-binding, coactivation, activation, apoptosis, and proliferation. Additional studies will use adenovirus to reconstitute mutated Gadd45¿ in the livers of null mice and test the importance of each separate function in hyperplasia. Aim 2 will address the diverse mechanisms by which CAR, a cis acting transcription factor, activates CAR- responsive regulatory regions of Fosl2. Experiments will also test whether Jun and Fosl2 are responsible for inducing hyperplasia, by studying TCPOBOP treatment in conditional Fosl2- and Jun-null mice, and by using adenovirus to induce liver expression vivo. Preliminary studies showed that Fosl2 and Jun combine to stimulate transcription of Cyclin D1 through a novel upstream regulatory region. Aim 3 will investigate the mechanisms that activate Cyclin D1 transcription and explain context-specific stimulation by Fosl2. Experiments will also determine the alternative pathways by which liver regeneration and T3-induced hyperplasia activate Cyclin D1 transcription. PUBLIC HEALTH RELEVANCE: The normal liver has several kinds of growth responses-some promote cancer while others inhibit promotion. These growth responses are very complex because they activate expression of hundreds of genes. The goals of this project are to define the common and distinctive parts of each response, and working from this comparison, determine a unique pathway of drug-induced proliferation and cancer promotion.

描述（由适用提供）：我们比较了激活肝脏中细胞增殖的四个过程：（1）肿瘤启动子TCPOBOP诱导的增生； （2）甲状腺激素诱导的抗抗肿瘤增生； （3）大鼠部分肝切开术（pH）后快速肝脏再生； （4）在小鼠中pH后pH后更多的更长时间的再生。该项目的第一阶段生成了所有四个过程的微阵列表达曲线的全面系统。 TCPOBOP是核接收器转录因子，CAR和快速诱导肝脏生长和细胞增殖的直接配体。 TCPOBOP处理后，表达曲线显示了GADD45，JUN和FOSL2 mRNA的快速诱导。我们专注于这三个基因的转录调节，以及细胞周期蛋白D1作为其下游靶标。 TCPOBOP治疗后，GADD45 null小鼠具有主动增殖，但转录和肝脏生长受损。分子研究表明，GADD45»直接结合CAR并充当转录共激活因子。这是GADD45的快速诱导是合成代谢的，可以使快速生长所需的高转录率。但是，其他研究人员发现GADD45`调节细胞凋亡和增殖。 AIM 1中提出的研究将通过确定其在转录复合物中的结合伴侣的结合伙伴以及对转录激活过程中进行性染色质重塑的作用，研究GADD45 g的GADD45如何可以充当共激活因子。其他实验将通过突变单个蛋白质结构域并测试每个实验对汽车结合，共激活，激活，凋亡和增殖的影响，从而确定GADD45如何具有如此多的关键功能。其他研究将使用腺病毒在无效小鼠的生命中重新构建突变的GADD45，并测试每个单独功能在增生中的重要性。 AIM 2将解决CAR（CIS COTING转录因子）激活FOSL2的CAR反应调节区的潜水机制。实验还将通过研究条件FOSL2和​​JUN-NULL小鼠的TCPOBOP处理以及使用腺病毒诱导肝脏表达体内来测试JUN和FOSL2是否负责诱导增生。初步研究表明，FOSL2和​​JUN结合通过新型的上游调节区域刺激细胞周期蛋白D1的转录。 AIM 3将研究激活细胞周期蛋白D1转录的机制，并解释FOSL2特定于上下文的模拟。实验还将确定肝脏再生和T3诱导的增生激活Cyclin D1转录的替代途径。公共卫生相关性：正常肝脏具有几种增长反应，几种促进癌症，而其他癌症则抑制促进。这些生长反应非常复杂，因为它们激活了数百个基因的表达。该项目的目标是定义每个响应的共同部分和独特的部分，并根据比较来确定药物诱导的增殖和癌症促进的独特途径。