SV40 and adenovirus may act as cocarcinogens by downregulating glutathione S-transferase expression.
We have discovered a novel function of the SV40 T antigen and the adenovirus E1A proteins: the ability to downregulate the endogenous expression of an important detoxification enzyme, glutathione S-transferase alpha (GST alpha). GST alpha mRNA is much less abundant in rat and human cells that express SV40 T antigen than in the parental cell lines. This GST alpha downregulation does not require expression of SV40 small t antigen or complex formation between large T antigen and p53, p300, or the pRb family of proteins. As might be predicted, cells that express SV40 T antigen are more sensitive than normal cells to alkylating drugs, which GST alpha is known to detoxify. Finally, GST alpha expression is also downregulated in cells that express the adenovirus E1A proteins. We propose that by downregulating GST alpha expression and inactivating p53 function, SV40 and adenovirus may contribute to the initiation of, or the progression toward, malignancy. Thus, in their quest to establish persistent infections, these viruses may inadvertently make the cellular environment more permissive for tumorigenesis.
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Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder 80309, USA. laurens@colorado.edu
D000256:Adenoviridae / Q000737:chemistry; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D002273:Carcinogens; D002460:Cell Line; D015536:Down-Regulation; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008466:Mechlorethamine / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D013539:Simian virus 40 / Q000737:chemistry; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D000477:Alkylating Agents; D000952:Antigens, Polyomavirus Transforming; D002273:Carcinogens; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008466:Mechlorethamine; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D005982:Glutathione Transferase