期刊
ONCOGENE
卷 25, 期 19, 页码 2727-2735出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209266
关键词
virus; DNA methylation; DNMT1; E2F; kidney
资金
- NCI NIH HHS [5T32 CA09676] Funding Source: Medline
- NIAID NIH HHS [AI060584] Funding Source: Medline
- NIDDK NIH HHS [DK61488] Funding Source: Medline
Many DNA tumor virus oncogenes are capable of activating and highjacking the host cell's DNA replication machinery for its own reproduction purposes through targeting and inactivation of the retinoblastoma pocket protein family. Pocket proteins function to regulate cell cycle progression and DNA synthesis through inhibitory interactions with the E2F transcription factors. The interaction of viral oncogenes with the pocket proteins is crucial for their transforming activity. We recently demonstrated that the DNA methyltransferase 1 (DNMT1) gene is an E2F target gene that is transcriptionally activated in cells lacking the retinoblastoma gene (Rb-/-). Overexpression of DNMT1 is implicated in tumor suppressor gene hypermethylation which is associated with tumorigenesis. Given that viral oncogenes potently stimulate E2F activity, we hypothesized that viral infection might activate DNMT1 and thereby promote transformation. Herein, we demonstrate that DNMT1 is strongly activated by the human polyomavirus BKV large T antigen (TAg) and adenovirus E1a. Viral oncogene mutants incapable of binding the pocket proteins are ineffective at activating DNMT1 compared to their wildtype counterparts. Additionally, mutation of the E2F sites within the DNMT1 promoters dramatically abrogates transcriptional activation. These data suggest that viral induction of DNMT1 through modulation of the pRB/E2F pathway may be involved in viral transformation.
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