DNA methyltransferase inhibition in normal human fibroblasts induces a p21-dependent cell cycle withdrawal

被引:53
作者
Young, JI
Smith, JR
机构
[1] Baylor Coll Med, Roy M & Phyllis Gough Huffington Ctr Aging, Dept Mol Virol & Microbiol, Houston, TX 77030 USA
[2] Baylor Coll Med, Roy M & Phyllis Gough Huffington Ctr Aging, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Baylor Coll Med, Roy M & Phyllis Gough Huffington Ctr Aging, Dept Med, Houston, TX 77030 USA
关键词
D O I
10.1074/jbc.M009470200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Maintenance of methylation patterns in the mammalian genome by DNA (cytosine-5) methyltransferases (DNAMeTase) is required for normal cell and tissue function, Inhibition of DNAMeTase in cultured cells induces the expression of p21, a cyclin-dependent kinase (Cdk) inhibitor critical for cells to enter replicative senescence, We investigated the effects of DNAMeTase inhibition in normal human fibroblasts and found that it induces an irreversible growth arrest. Cells arrested by DNAMeTase inhibition became enlarged and had a flat morphology, exhibited an increased expression of collagenase and p21, and the DNA synthesis block could be overcome by the introduction of the SV40 large T antigen, all characteristics of senescent cells. In contrast, normal human fibroblasts lacking a functional p21 gene fail to undergo cell cycle arrest following DNAMeTase inhibition, indicating that p21 is an essential component of this arrest. Furthermore, DNAMeTase activity was reduced as cells approached the end of their proliferative potential. These data suggest that DNAMeTase could be an integral part of the mechanisms by which cells count the number of cell divisions completed and initiate a signaling cascade that ultimately results in the senescent phenotype.
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收藏
页码:19610 / 19616
页数:7
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