Abstract
Bcl-2 stimulates mutagenesis after the exposure of cells to DNA-damaging agents. However, the biological mechanisms of Bcl-2-mediated mutagenesis have remained largely obscure. Here we demonstrate that the Bcl-2-mediated suppression of hMSH2 expression results in a reduced cellular capacity to repair mismatches. The pathway linking Bcl-2 expression to the suppression of mismatch repair (MMR) activity involves the hypophosphorylation of pRb, and then the enhancement of the E2F-pRb complex. This is followed by a decrease in hMSH2 expression. MMR has a key role in protection against deleterious mutation accumulation and in maintaining genomic stability. Therefore, the decreased MMR activity by Bcl-2 may be an underlying mechanism for Bcl-2-promoted oncogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Pair Mismatch
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CDC2-CDC28 Kinases / metabolism
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Cell Cycle Proteins / metabolism*
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Cells, Cultured
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Cyclin-Dependent Kinase 2
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DNA Repair*
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DNA-Binding Proteins / metabolism*
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Down-Regulation
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E2F Transcription Factors
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Gene Expression Regulation, Neoplastic
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Humans
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MutS Homolog 2 Protein
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Mutagenesis
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Mutation
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Neoplasms / genetics
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Phosphorylation
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Retinoblastoma Protein / metabolism
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Transcription Factors / metabolism*
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Transcription, Genetic
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Retinoblastoma Protein
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Transcription Factors
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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MSH2 protein, human
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MutS Homolog 2 Protein