Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity.
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.
Mesh Terms:
Base Pair Mismatch, CDC2-CDC28 Kinases, Cell Cycle Proteins, Cells, Cultured, Cyclin-Dependent Kinase 2, DNA Repair, DNA-Binding Proteins, Down-Regulation, E2F Transcription Factors, Gene Expression Regulation, Neoplastic, Humans, MutS Homolog 2 Protein, Mutagenesis, Mutation, Neoplasms, Phosphorylation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Retinoblastoma Protein, Transcription Factors, Transcription, Genetic
Base Pair Mismatch, CDC2-CDC28 Kinases, Cell Cycle Proteins, Cells, Cultured, Cyclin-Dependent Kinase 2, DNA Repair, DNA-Binding Proteins, Down-Regulation, E2F Transcription Factors, Gene Expression Regulation, Neoplastic, Humans, MutS Homolog 2 Protein, Mutagenesis, Mutation, Neoplasms, Phosphorylation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Retinoblastoma Protein, Transcription Factors, Transcription, Genetic
Nat. Cell Biol.
Date: Feb. 01, 2005
PubMed ID: 15619620
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