Abstract
Overexpression of c-Myc is one of the most common alterations in human cancers, yet it is not clear how this transcription factor acts to promote malignant transformation. To understand the molecular targets of c-Myc function, we have used an unbiased genome-wide location-analysis approach to examine the genomic binding sites of c-Myc in Burkitt's lymphoma cells. We find that c-Myc together with its heterodimeric partner, Max, occupy >15% of gene promoters tested in these cancer cells. The DNA binding of c-Myc and Max correlates extensively with gene expression throughout the genome, a hallmark attribute of general transcription factors. The c-Myc/Max heterodimer complexes also colocalize with transcription factor IID in these cells, further supporting a general role for overexpressed c-Myc in global gene regulation. In addition, transcription of a majority of c-Myc target genes exhibits changes correlated with levels of c-myc mRNA in a diverse set of tissues and cell lines, supporting the conclusion that c-Myc regulates them. Taken together, these results suggest a general role for overexpressed c-Myc in global transcriptional regulation in some cancer cells and point toward molecular mechanisms for c-Myc function in malignant transformation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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Burkitt Lymphoma / genetics
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Burkitt Lymphoma / metabolism*
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Cell Transformation, Neoplastic / genetics
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / physiology
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Dimerization
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Genes, myc*
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Humans
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / physiology*
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Oligonucleotide Array Sequence Analysis
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Promoter Regions, Genetic / genetics
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Protein Interaction Mapping
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Proto-Oncogene Proteins c-myc / chemistry
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Proto-Oncogene Proteins c-myc / physiology*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Transcription Factor TFIID / physiology
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Transcription Factors*
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Transcription, Genetic*
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Translocation, Genetic
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Tumor Cells, Cultured / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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MAX protein, human
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Myc associated factor X
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Neoplasm Proteins
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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RNA, Neoplasm
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Transcription Factor TFIID
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Transcription Factors