Abstract
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 wild-type 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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / virology
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Adenovirus E1A Proteins / metabolism
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / metabolism
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BK Virus / physiology*
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Cell Transformation, Viral*
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Cells, Cultured
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism*
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism*
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Enzyme Activation
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Humans
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Luciferases
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Male
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Mice
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Mice, Knockout
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Mutation
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NIH 3T3 Cells / metabolism
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NIH 3T3 Cells / virology
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Polyomavirus Infections / immunology
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Polyomavirus Infections / virology
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Promoter Regions, Genetic / genetics
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / virology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Transcription, Genetic
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Transcriptional Activation
Substances
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Adenovirus E1A Proteins
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Antigens, Polyomavirus Transforming
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E2F Transcription Factors
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RNA, Messenger
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Retinoblastoma Protein
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Luciferases
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNMT1 protein, human
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Dnmt1 protein, mouse