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，突变基因引起癌症的背景/OUTLINETHE范式已成为我研究的指导原理。环境因素在癌症因果关系中的影响是基于其诱变能力改变癌症基因，从而导致癌基因的激活以及消除或消除肿瘤抑制肿瘤基因。癌症从初期恶性细胞到侵袭性肿瘤的发展，最后是转移肿瘤，这是由达尔文式扩展的克隆细胞种群的扩展驱动的，涉及其他突变的癌症基因。我们的研究计划始于1987年，最终达到了1993年的VHL TSG的标识，位于3p25。在1993 - 2003年，我们研究了VHL基因的序列结构，并鉴定并分析了VHL靶基因以发现VHL途径。同时，我们加强了对位于3p26、3p21.3和3p12癌症基因的映射和分子克隆的研究，参与了主要形式的肺癌和肾脏，乳房和前列腺的其他常见癌的起源和/或开发。在2000 - 2003年，我们研究了：（1）VHL基因座本身的甲基化代码以及VHL靶基因的功能（碳酸酐酶，Ca9和Ca12，以及转录调节剂BHLHB2/Stra13）； （2）通过肿瘤组织和细胞系中实时PCR在3P21.3中的持续缺失映射，并完成了从3p21.3区域（Centromeric，Luca和Telomeric，AP20）的候选癌症引起癌症基因的分离和初始表征。这些3P21.3区域（Centromeric，Luca和Telomeric，AP20）应视为连续的癌症基因区域，因为每个候选TSG都有群集。 （3）我们还确定了3p26.3和3p12.3in 2003-2005中的候选癌基因，我们将研究重点放在功能分析上（通过发现相互作用的蛋白质，分析小鼠中的无效突变体以及对这些候选者TSG的生物信息学注释）。癌症基因调用（3p26）基因，请致电3p26.3编码能够同型和异型结合的跨内膜细胞粘附分子（CAM），我们在1998年克隆了我们在1998年克隆的，与一般认知活性（G/iq）相关（ieq），以及脑疾病的一般性疾病（i。在各种人类肿瘤中过表达。最近显示，一个3P26基因组段（包含两个基因，CALL和CNTN6）具有前列腺癌敏感性的候选前列腺癌家族，尽管在两个居住基因中均未检测到突变。我们的表达研究表明，呼叫可能有助于癌症的侵入性生长和转移（根据阶段，它可以用作“肿瘤抑制剂”或“癌基因”）。我们假设在初始生长期间未表达（沉默）肿瘤细胞以促进原位肿瘤生长。在肿瘤质量边缘的呼叫重新表达可以促进局部侵入性生长，此外，肿瘤细胞可以进入并留下血液，定居遥远的组织并建立转移性肿瘤。当前的工作和计划​​：我们正在开发特定的抗体，并将验证呼吁作为侵入性肿瘤生长和转移的生物标志物，以及在白血病，黑色素瘤，黑色素瘤以及一些肺癌和卵巢癌过度表达的呼叫的新颖目标。 CpG癌基因的启动子岛现在被接受为癌变的基本机制。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代码（CPG和组蛋白代码）来了解它们是否具有与个体间差异相关的变化，这可能决定了零星癌的风险。