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.
Department of Microbiology, University of Texas Health Science Center, San Antonio 78284-7758.
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Martin
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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