A DNA microarray screen for genes involved in c-MYC and N-MYC oncogenesis in human tumors.
MYC proto-oncogenes play a major role in various types of human tumors. The products of these genes are transcription factors that bind to specific sequences and activate the expression of target genes. Identifying these target genes and their downstream effectors is a crucial step in understanding and preventing MYC induced oncogenesis. Until now, most of the efforts to identify such genes were performed by analysing in vitro systems whose relevance to the malignant process in vivo remains unclear. We aimed at identifying genes that play a major role in the malignant process of MYC induced carcinogenesis. Thus, we analysed the expression profiles of human MYC induced tumors and compared them to similar, non-MYC tumors. Moreover, we looked for the common characteristics of different types of MYC induced tumors. We identified several genes, most of them involved in cell cycle regulation, that are over expressed in MYC induced lymphomas as well as MYC induced neuronal-like tumors. In order to determine whether MYC induced oncogenesis is similar in human and in the mouse model system, we analysed the expression of the identified genes in cells derived from transgenic mice tumors. We also present the distribution of MYC putative binding sites in the regulatory sequences of the genes identified in our analysis. This analysis pointed to two genes (E2F1 and TSC2) as candidates to be targets of Myc activity. We thus further analysed the expression of these genes in the tumor cell lines, and examined the plausibility that elements in their promoter bind the Myc protein. Our data points to several genes that may be involved in c-MYC and N-MYC induced tumors and to two genes that may be targets for MYC activity.
Schuldiner
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O
Department of Genetics, The Silberman Institute for Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
Benvenisty
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N
D000818:Animals; D001932:Brain Neoplasms / Q000209:etiology / Q000378:metabolism; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000209:etiology / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; C493755:E2f1 protein, rat; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins