Role Of CTCF In Tumor Development

CTCF 在肿瘤发展中的作用

• 批准号: 6507005
• 负责人: VICTOR LOBANENKOV
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6507005
• 关键词: DNA methylation; Wilms' tumor; breast neoplasms; gene induction /repression; gene mutation; genetic promoter element; genomic imprinting; neoplasm /cancer genetics; prostate neoplasms; protooncogene; tissue /cell culture; transcription factor

The Molecular Pathology Section (MPS) lead by Dr. Victor V. Lobanenkov within the Laboratory of Immunopathology (LIP) NIAID was established in September 1999. Dr. V. Lobanenkov received Master Degree in Nuclear Physics from the Institute of Physics and Engineering in 1977, switched to cancer biology as a second field of study, and received his Ph.D. degree in experimental oncology from the Cancer Research Center in Moscow in 1981. Following his work at the Royal Cancer Hospital in London, he was appointed as a Head of Molecular Carcinogenesis group at the Institute of Carcinogenesis: All-Union Cancer Center of the former USSR and a Visiting Scholar at the Institute of Cancer Research, Royal Cancer Hospital of London. In 1990, he was invited to work at the Fred Hutchinson Cancer Research Center in Seattle, WA where he held a position of the Foreign Faculty in Residence with an independent research agenda funded by NIH/NCI RO1 grants until moving to NIH in 1999. Most of the research projects carried out in LIP MPS are focused on structure and function of CTCF gene that was identified and cloned by V. Lobanenkov and co-workers in 1990, and was initially characterized as an evolutionarily conserved negative transcriptional regulator of vertebrate MYC oncogenes. CTCF contains 11 Zn finger (ZF) DNA-binding domain conserved from Drosophila to frogs to birds to mice to men. Different CTCF-target sites (CTSs), recognized by different combinations of CTCF ZFs, perform distinct regulatory functions. Depending on the context, different CTSs play distinct roles in transcriptional regulation by CTCF including promoter repression, activation, and creation of the thyroid hormone-responsive silencers. These studies resulted in more then 30 publications, and the USA and foreign Patents issued in 1999. The very first review on CTCF published in "Trends in Genetics" in 2001 by V. Lobanenkov and his major collaborators from Germany and Sweden, provides a summary of experimental results which together show that CTCF is a uniquely versatile transcriptional regulator with diverse functions linked to epigenetics and disease. It is an exceptionally evolutionarily conserved Zinc Finger (ZF) phosphoprotein that binds via combinatorial utilization of the eleven ZFs to ~ 50 bp long DNA target sites with remarkable sequence variation. Formation of different CTCF-DNA complexes, a subset of which is CpG-methylation-sensitive, results in distinct functions including gene activation, repression, silencing or chromatin insulation. Disrupting the spectrum of target specificities by ZF mutations or by abnormal selective methylation of certain CTCF-targets is associated with cancer. CTCF emerged, therefore, as a central player in networks linking expression domains with epigenetics and cell growth regulatory processes. It is thus not surprising that in recent years there has been a rapidly growing interest in the CTCF gene. Besides LIP NIAID, different aspects of CTCF biology have become a major focus of research in several other laboratories both within and outside NIH, and abroad. In 2000-01, MPS LIP continued to work on a program directed to better understanding of CTCF normal function in development, cell-cycle regulation, and gene imprinting; and of CTCF malfunction in cancer, and in other human diseases associated with abnormal site-specific DNA methylation (for instance, in congenital myotonic dystrophy). This program takes advantage of cancer-prone mouse CTCF knock-out models, and of Drosophila genetics based on identification and cloning of the CTCF homologue in flies. Several new publications, including those in "Cancer Research" and in "Nature Genetics", came out in 2001, while several more are being submitted. Identification and functional characterization of cancer-associated CTCF mutations can be viewed as experiments of Nature that reveal critically important CTCF target genes and protein partners that are involved in regulation of CTCF function. Identifying such genes and partners reveals regulatory gene networks and pathways which define tumor phenotype(s), and thus leads the Molecular Pathology Section well beyond studies of CTCF per se because novel genes in a pathway of mutant CTCF are to be, in turn, potential oncogenes or tumor suppressor genes. By September 2001, some of these proprietary genes have already been characterized and are now being patented by NIAID NIH, and evaluated for diagnostic and therapeutic purposes. Several other genes encoding CTCF-interacting proteins are at the initial stages of deciphering their role(s).

NIAID免疫病理学实验室（LIP）内由维克托V. Lobanenkov博士领导的分子病理学部门（MPS）成立于1999年9月。V. Lobanenkov博士于1977年获得物理与工程研究所核物理学硕士学位，之后转向癌症生物学作为第二研究领域，并获得博士学位。1981年在莫斯科癌症研究中心获得实验肿瘤学学位。在伦敦皇家癌症医院工作后，他被任命为致癌研究所分子致癌小组负责人：前苏联全联盟癌症中心和伦敦皇家癌症医院癌症研究所访问学者。1990年，他被邀请到位于华盛顿州西雅图的弗雷德哈钦森癌症研究中心工作，在那里他担任外国驻校教师，拥有由NIH/NCI RO 1赠款的独立研究议程，直到1999年搬到NIH。 CTCF基因是1990年由V. Lobanenkov等发现并克隆的，最初被认为是脊椎动物MYC癌基因的一个进化上保守的负转录调控因子。CTCF含有11个锌指（ZF）DNA结合结构域，从果蝇到青蛙到鸟类到小鼠到人类都是保守的。由CTCF ZF的不同组合识别的不同CTCF靶位点（CTS）执行不同的调节功能。根据上下文，不同的CTS在CTCF的转录调控中发挥不同的作用，包括启动子抑制、激活和甲状腺激素应答沉默子的产生。这些研究产生了30多篇出版物，并在1999年发布了美国和外国专利。 2001年，V. Lobanenkov及其来自德国和瑞典的主要合作者在“Trends in Genetics”上发表了关于CTCF的第一篇综述，提供了实验结果的总结，这些结果共同表明CTCF是一种独特的多功能转录调节因子，具有与表观遗传学和疾病相关的多种功能。它是一种在进化上非常保守的锌指（ZF）磷蛋白，其通过组合利用11个ZF结合至具有显著序列变异的约50 bp长的DNA靶位点。不同的CTCF-DNA复合物的形成，其中一个子集是CpG甲基化敏感的，导致不同的功能，包括基因激活，抑制，沉默或染色质绝缘。ZF突变或某些CTCF靶点的异常选择性甲基化破坏靶点特异性谱与癌症相关。因此，CTCF成为连接表达结构域与表观遗传学和细胞生长调控过程的网络中的核心参与者。 因此，近年来人们对CTCF基因的兴趣迅速增长也就不足为奇了。除了LIP NIAID，CTCF生物学的不同方面已经成为NIH内外其他几个实验室和国外研究的主要焦点。 在2000-01年，MPS LIP继续致力于一项旨在更好地了解CTCF在发育、细胞周期调节和基因印记中的正常功能的计划;以及癌症和与异常位点特异性DNA甲基化相关的其他人类疾病（例如，先天性肌强直性营养不良）中的CTCF功能障碍。该项目利用了易患癌症的小鼠CTCF基因敲除模型，以及基于果蝇中CTCF同源物的鉴定和克隆的果蝇遗传学。2001年出版了几份新的出版物，包括《癌症研究》和《自然遗传学》上的出版物，还有几份正在提交中。 癌症相关CTCF突变的鉴定和功能表征可以被视为自然实验，其揭示了参与调节CTCF功能的至关重要的CTCF靶基因和蛋白质伴侣。识别这些基因和合作伙伴揭示了调控基因网络和途径，定义肿瘤表型（S），从而导致分子病理学部分远远超出CTCF本身的研究，因为新的基因突变CTCF的途径，反过来，潜在的癌基因或肿瘤抑制基因。到2001年9月，这些专利基因中的一些已经得到鉴定，现在由NIAID NIH申请专利，并进行诊断和治疗评估。编码CTCF相互作用蛋白的其他几个基因正处于破译其作用的初始阶段。