C MYC TARGETS IN THE PATHOGENESIS OF HUMAN CANCERS

描述：（改编自申请人的摘要）c-myc基因是一种 最高度改变的癌基因。与正常细胞相比， 其中c-myc表达受到调节，c-myc基因的表达被 在许多类型的人类癌症中是组成性的。c-Myc蛋白质二聚化， 最大结合特定的DNA位点和调节转录。进一步 为了了解c-Myc的转化机制，他试图确定 c-Myc靶基因。在过去的融资期间，他的策略是利用 代表性差异分析成功地确定了一些 生物学相关的Myc靶基因。采用简化的方法，他 发现c-Myc调节乳酸脱氢酶A的表达， 糖酵解增强，这是一种在癌症中普遍存在的表型。他还 发现了两个新的Myc靶基因，Rcl和JP 1， 锚定非依赖性生长类似于c-Myc诱导的表型。 虽然这些Myc靶基因的产物部分地概括了Myc 功能，其生化功能是未知的。他的策略已经屈服了 重要的见解;然而，很明显，一个有重点的， 简化的方法没有考虑到之间的合作 c-Myc靶基因诱导特异性c-Myc介导的表型。因此， 采取了一种综合的方法，并开始使用cDNA微阵列分析， 鉴定由c-Myc上调或下调的基因组。 通过这一策略，他将确定c-Myc，其 靶基因和Myc介导的表型。他处于一个独特的位置来定义 与c-Myc过表达相关的基因表达模式，并希望 这些信息将有助于癌症的分子分类。达成 长期目标是了解c-Myc诱导的转录程序 在人类癌症中，他设定了以下目标：（1）进一步表征rcl 和JP 1的表达，并鉴定其生化功能;（2）鉴定直接的c-Myc 使用诱导型c-Myc系统的靶基因，并鉴定c-Myc靶基因 通过组蛋白乙酰化或甲基化调节;和（3） 鉴定表达的c-Myc转录靶的子集 与肿瘤组织类型无关。

DESCRIPTION: (Adapted from applicant's abstract) The c-myc gene is one of the most highly altered oncogene in human cancers. In contrast to normal cells, in which c-myc expression is regulated, expression of the c-myc gene is constitutive in many types of human cancers. The c-Myc protein dimerizes with Max to bind specific DNA sites and regulate transcription. To further understand the mechanisms of transformation by c-Myc, he sought to identify c-Myc target genes. In the past funding period, his strategy using representational difference analysis was successful in identifying a number of biologically relevant Myc target genes. Taking a reductionistic approach, he discovered that c-Myc regulates lactate dehydrogenase A expression and causes enhanced glycolysis, a phenotype that is prevalent among cancers. He also discovered two novel Myc target genes, Rcl and JP1, which induce anchorage-independent growth resembling the phenotype induced by c-Myc. Although the products of these Myc target genes partially recapitulate Myc function, their biochemical functions are unknown. His strategy has yielded important insights; however, it has become apparent that a focused, reductionistic approach does not take into account the collaborations among c-Myc target genes to induce specific c-Myc mediated phenotypes. Hence, he has taken an integrative approach and have begun to use cDNA microarray analyses to identify sets of genes that are either up-regulated or down-regulated by c-Myc. Through this strategy, he will identify additional links between c-Myc, its target genes and Myc mediated phenotypes. He is in a unique position to define gene expression patterns that are related to c-Myc overexpression and hope that this information will help in the molecular classification of cancers. To reach the long term goal of understanding the transcription program induced by c-Myc in human cancers, he sets the following aims: (1) To further characterize rcl and JP1 and identify their biochemical functions; (2) To identify direct c-Myc target genes using an inducible c-Myc system and to identify c-Myc target genes that are regulated through histone acetylation or methylation; and (3) To identify a subset of c-Myc transcriptional targets that is expressed independently of tumor tissue type.