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.
Youn
Cha-Kyung
CK
Department of Pharmacology, School of medicine, Chosun University, 375 Seusuk-dong, Gwangju 501-759, South Korea.
Cho
Hyun-Ju
HJ
Kim
Soo-Hyun
SH
Kim
Hong-Beum
HB
Kim
Mi-Hwa
MH
Chang
In-Youb
IY
Lee
Jung-Sup
JS
Chung
Myung-Hee
MH
Hahm
Kyung-Soo
KS
You
Ho Jin
HJ
D020137:Base Pair Mismatch; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D050684:E2F Transcription Factors; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051718:MutS Homolog 2 Protein; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein