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.
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