Functional Analysis of Cancer Genes from Human Chromosom

人类染色体癌症基因的功能分析

• 批准号: 7291849
• 负责人: MICHAEL LERMAN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/7291849
• 关键词: Functional; Analysis; Cancer; Genes; Human

Background/outlineThe paradigm that mutated genes cause cancer has become a guiding principle in my research since 1980. The effect of environmental factors in cancer causation is based on their mutagenic capability to alter cancer-prone genes leading to activation of oncogenes and elimination or silencing of tumor suppressor genes. The development of cancer from incipient malignant cells to invasive tumors and finally to metastases is driven by Darwinian expansion of clonal cell populations involving additional mutated cancer genes. Our research program began in 1987 and culminated in the identification in 1993 of the VHL TSG located at 3p25. In 1993-2003 we investigated the sequence structure of the VHL gene and identified and analyzed VHL target genes to discover the VHL pathway. In parallel we intensified research on mapping and molecular cloning of cancer genes located in 3p26, 3p21.3 and 3p12 involved in the origin and/or development of major forms of lung cancer and other common carcinomas of the kidney, breast and prostate. In 2000-2003 we investigated: (1) the methylation code of the VHL locus itself and the function of VHL target genes (carbonic anhydrases, CA9 and CA12, and the transcription regulator BHLHB2/STRA13); (2) continued deletion mapping in 3p21.3 by real time PCR in tumor tissues and cell lines and completed the isolation and initial characterization of candidate cancer-causing genes from both 3p21.3 regions (centromeric, LUCA, and telomeric, AP20). These 3p21.3 regions (centromeric, LUCA, and telomeric, AP20) should be considered contiguous cancer gene regions since each harbors clusters of candidate TSG. (3) We also identified candidate cancer genes in 3p26.3 and 3p12.3In 2003-2005 we focused our research on functional analysis (by finding interacting proteins, analyzing null mutants in mice, and bioinformatics annotations) of some of these candidate TSG. Cancer gene CALL (3p26)The gene, CALL on 3p26.3 encoding a trans-membrane cell adhesion molecule (CAM) capable of both homotypic and heterotypic binding, that we cloned in 1998 was shown to be involved in general cognitive activities (g/IQ) and some neurological diseases (i.e. schizophrenia).CALL is expressed in normal tissues beside the brain and is over-expressed in a variety of human tumors. A 3p26 genomic segment (containing two genes, CALL and CNTN6) was recently shown to harbor a candidate for prostate cancer susceptibility in Finish prostate cancer families although no mutations were detected in both residing genes. Our expression studies suggest that CALL may contribute to cancer invasive growth and metastasis (depending on stage it may act either as a "tumor suppressor" or "oncogene"). We hypothesize that during initial growth CALL is not expressed (silenced) in tumor cells to facilitate in situ tumor growth. Re-expression of CALL on the edge of the tumor mass could promote local invasive growth and furthermore allow tumor cells to enter and leave the blood stream, colonize distant tissues and establish metastatic tumors. Current work and plans: We are developing specific antibodies and will validate CALL as a biomarker of invasive tumor growth and metastasis and a novel target for immune intervention in leukemia, melanoma, and some lung and ovarian cancers over-expressing CALL.We also plan to analyze CALL for miRNA mutations in sporadic prostate and other cancers.VHL TSG (3p25)Aberrant methylation of CpG promoter islands of cancer genes is now accepted as a fundamental mechanism in carcinogenesis. Using the VHL locus as a model system, we investigated the mechanisms of aberrant DNA methylation in cancer. We also aimed to use epigenetic codes (CpG and histone codes) to understand whether they harbor variations associated with inter-individual differences that may determine risk of sporadic cancers.

自1980年以来，突变基因导致癌症的范式已成为我研究的指导原则。环境因素在癌症病因中的作用是基于它们改变致癌基因的诱变能力，从而导致癌基因的激活和肿瘤抑制基因的消除或沉默。癌症从初期恶性细胞到侵袭性肿瘤并最终到转移的发展是由涉及额外突变的癌症基因的克隆细胞群体的达尔文扩张驱动的。我们的研究计划始于1987年，并在1993年鉴定出位于3 p25的VHL TSG。1993年至2003年，我们研究了VHL基因的序列结构，并鉴定和分析了VHL靶基因，以发现VHL通路。与此同时，我们加强了对位于3 p26、3p21.3和3 p12的癌症基因的定位和分子克隆的研究，这些基因涉及主要形式的肺癌和其他常见的肾癌、乳腺癌和前列腺癌的起源和/或发展。2000-2003年我们研究了：（1）VHL基因座本身的甲基化密码和VHL靶基因的功能（碳酸酐酶，CA 9和CA 12，以及转录调节子BHLHB 2/STRA 13）;（2）通过真实的时间PCR在肿瘤组织和细胞系中继续进行3p21.3的缺失定位，并完成候选癌症的分离和初步表征-引起来自两个3p21.3区域的基因（着丝粒的LUCA和端粒的AP 20）。这些3p21.3区域（着丝粒的LUCA和端粒的AP 20）应被认为是连续的癌症基因区域，因为每个区域都含有候选TSG的簇。(3)我们还确定了3p26.3和3p12.3中的候选癌基因。2003-2005年，我们将研究重点放在这些候选TSG的功能分析（通过寻找相互作用的蛋白质，分析小鼠中的无效突变体和生物信息学注释）上。癌基因CALL（3 p26）我们于1998年克隆了位于3p26.3上的CALL基因，该基因编码一种能够进行同型和异型结合的跨膜细胞粘附分子（CAM），该基因被证明与一般认知活动（g/IQ）和一些神经系统疾病（即精神分裂症）有关。3 p26基因组片段（包含两个基因，CALL和CNTN 6）最近被证明是Finish前列腺癌家族中前列腺癌易感性的候选者，尽管在两个驻留基因中均未检测到突变。我们的表达研究表明，CALL可能有助于癌症的侵袭性生长和转移（取决于阶段，它可能作为“肿瘤抑制因子”或“癌基因”）。我们假设在初始生长期间，CALL在肿瘤细胞中不表达（沉默）以促进原位肿瘤生长。CALL在肿瘤块边缘的重新表达可以促进局部侵袭性生长，并且进一步允许肿瘤细胞进入和离开血流，定殖远处组织并建立转移性肿瘤。目前的工作和计划：我们正在开发特异性抗体，并将验证CALL作为侵袭性肿瘤生长和转移的生物标志物以及白血病，黑色素瘤，我们还计划分析散发性前列腺癌和其他癌症中CALL的miRNA突变。VHL TSG（3 p25）癌基因启动子区CpG岛的异常甲基化是肿瘤发生的一个重要机制。使用VHL基因座作为模型系统，我们研究了癌症中异常DNA甲基化的机制。我们还旨在使用表观遗传密码（CpG和组蛋白密码）来了解它们是否含有与个体间差异相关的变异，这些变异可能决定散发性癌症的风险。