Abstract
Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of gammaH2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Ataxia Telangiectasia / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Western
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Caspase 3
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Caspases / metabolism
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Cell Cycle Proteins / metabolism
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Cell Cycle Proteins / physiology*
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Cell Line
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Cell Line, Tumor
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Cells, Cultured
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Chromosomal Proteins, Non-Histone / metabolism
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Comet Assay
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DNA Damage
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Female
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Fibroblasts / metabolism
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Genotype
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Histones / chemistry
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Humans
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Immunoblotting
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Immunohistochemistry
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Keratinocytes / cytology
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Keratinocytes / metabolism
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Lymphoma / metabolism
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Male
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Mice
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Fluorescence
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Neoplasms / metabolism
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Neoplasms / pathology*
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Oncogenes
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins c-myc / metabolism*
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Thymus Gland / pathology
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Time Factors
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / physiology*
Substances
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Cell Cycle Proteins
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Histones
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Proto-Oncogene Proteins c-myc
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Tumor Suppressor Proteins
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gamma-H2AX protein, mouse
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structural maintenance of chromosome protein 1
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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CASP3 protein, human
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Casp3 protein, mouse
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Caspase 3
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Caspases