Inhibition of viral and cellular promoters by human wild-type p53.
Mutation of the p53 tumor suppressor gene is a recurring event in a variety of human cancers. Wild-type p53 may regulate cell proliferation and has recently been shown to repress transcription from several cellular promoters. We studied the effects of wild-type and mutant human p53 on the human proliferating-cell nuclear antigen promoter and on several viral promoters including the simian virus 40 early promoter-enhancer, the herpes simplex virus type 1 thymidine kinase and UL9 promoters, the human cytomegalovirus major immediate-early promoter-enhancer, and the long terminal repeat promoters of Rous sarcoma virus, human immunodeficiency virus type 1, and human T-cell lymphotropic virus type I. HeLa cells were cotransfected with a wild-type or mutant p53 expression vector and plasmids containing a chloramphenicol acetyltransferase reporter gene under viral (or cellular) promoter control. Expression of wild-type p53 correlated with a consistent and significant (6- to 76-fold) reduction of reporter enzyme activity. A mutation at amino acid 143 of p53 releases this inhibition significantly with all the promoters studied. Expression of a p53 mutated at any one of the five amino acid positions 143, 175, 248, 273, and 281 also correlated with a much smaller (one- to sixfold) reduction of reporter enzyme activity from the herpes simplex virus type 1 thymidine kinase promoter. These mutant forms of p53 are found in various cancer cells. Thus, failure of tumor suppression correlates with loss of the promoter inhibitory effect of p53.
Subler
M A
MA
Department of Microbiology, University of Texas Health Science Center, San Antonio 78284-7758.
Martin
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DW
Deb
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D000951:Antigens, Neoplasm / Q000235:genetics; D001358:Avian Sarcoma Viruses / Q000235:genetics*; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D016158:Genes, p53; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D010957:Plasmids; D018809:Proliferating Cell Nuclear Antigen; D011401:Promoter Regions, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D013539:Simian virus 40 / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D014158:Transcription, Genetic
D000951:Antigens, Neoplasm; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D015500:Chloramphenicol O-Acetyltransferase; D013937:Thymidine Kinase