The transcriptional basis of tumor promotion

肿瘤促进的转录基础

• 批准号: 8462567
• 负责人: JOSEPH D LOCKER
• 金额: $ 31.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462567
• 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; 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

PROJECT SUMMARY 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 nul 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.

项目摘要 我们比较了激活肝脏细胞增殖的四个过程：（1）增生 （2）由肿瘤促进剂TCPOBOP诱导的抗促进性增生; （3）大鼠肝部分切除术后肝再生迅速; （4）PH后再生时间延长。第一阶段 项目产生了一个全面的系统的微阵列表达谱的所有四个 流程. TCPOBOP是核受体转录因子CAR的直接配体， 并迅速诱导肝脏生长和细胞增殖。表达谱显示， TCPOBOP处理后Gadd 45 <$、Jun和Fosl 2 mRNA的快速诱导; 集中在这三个基因的转录调控，并在细胞周期蛋白D1作为他们的 下游目标TCPOBOP后，Gadd 45-null小鼠具有活跃的增殖 治疗，但受损的转录和肝脏生长。分子研究表明， Gadd 45直接结合CAR并作为转录辅激活因子。因此，快速 Gadd 45 <$的诱导是合成代谢的，并使转录所需的高速率， 快速增长。然而，其他研究人员发现Gadd 45调节细胞凋亡， 和扩散。目标1中提出的研究将调查Gadd 45 â（仅18岁）如何 kD，可以作为一个辅激活剂，通过确定其结合配偶体中的 转录复合物，及其对进行性染色质重塑的影响， 转录激活其他实验将确定Gadd 45是如何做到这一点的 许多关键功能，通过突变个别蛋白质结构域，并测试每个 对CAR结合、共活化、活化、凋亡和增殖的影响。额外 研究将使用腺病毒在裸小鼠的肝脏中重建突变的Gadd 45 并测试增生中每种独立功能的重要性。目标2将解决 CAR是一种顺式作用转录因子，通过多种机制激活CAR-1。 Fosl 2的响应调节区。实验还将测试Jun和Fosl 2是否 负责诱导增生，通过研究TCPOBOP治疗条件 Fosl 2-和Jun-null小鼠，并通过使用腺病毒体内诱导肝脏表达。 初步研究表明，Fosl 2和Jun联合收割机可以刺激转录， 细胞周期蛋白D1通过一个新的上游调控区。目标3将调查 激活细胞周期蛋白D1转录并解释环境特异性 Fosl 2的刺激。实验还将确定替代途径， 肝再生和T3诱导增生激活细胞周期蛋白D1转录。

项目成果

Proteomic characterization of early changes induced by triiodothyronine in rat liver.

大鼠肝脏中三碘甲醇引起的早期变化的蛋白质组学表征。

• DOI: 10.1021/pr200244f
• 发表时间: 2011-07-01
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Severino, Valeria;Locker, Joseph;Ledda-Columbano, Giovanna M.;Columbano, Amedeo;Parente, Augusto;Chambery, Angela
• 通讯作者: Chambery, Angela

Binding of Drug-Activated CAR/Nr1i3 Alters Metabolic Regulation in the Liver.

药物激活的CAR/NR1I3的结合改变了肝脏中的代谢调节。

• DOI: 10.1016/j.isci.2018.10.018
• 发表时间: 2018-11-30
• 期刊: iScience
• 影响因子: 5.8
• 作者: Tian J;Marino R;Johnson C;Locker J
• 通讯作者: Locker J

Mechanism and Effect of HNF4α Decrease in a Rat Model of Cirrhosis and Liver Failure.

• DOI: 10.1016/j.jcmgh.2023.11.009
• 发表时间: 2024
• 期刊: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
• 影响因子: 7.2
• 作者: Melis, Marta;Marino, Rebecca;Tian, Jianmin;Johnson, Carla;Sethi, Rahil;Oertel, Michael;Fox, Ira J.;Locker, Joseph
• 通讯作者: Locker, Joseph