title: RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome.
abstract: RNA polymerase (pol) III synthesizes essential small RNAs, including tRNA and 5S rRNA. Wild-type p53 can repress pol III transcription both in vitro and in vivo. Many tumours carry substitutions in p53 which have selective effects on its functions. We identify tumour-derived mutations that compromise the ability of p53 to regulate pol III transcription. Furthermore, substitution R175H, the most common mutation in cancers, converts p53 from a repressor to an activator of pol III. Oncoproteins neutralize p53 in some tumours; we show that human papillomavirus E6 and cellular hdm2 can both release pol III from repression by p53. These data suggest that the restraining influence of p53 on pol III will be lost in many tumours. In addition to these features of sporadic cancers, some individuals inherit mutant forms of p53 and consequently suffer from Li-Fraumeni syndrome, showing genetic predisposition to certain malignancies. We find that pol III transcriptional activity is often highly elevated in primary fibroblasts from Li-Fraumeni patients, especially if the germline p53 mutation is followed by loss of the remaining allele. Our data suggest that p53 status can have a profound effect upon pol III transcription and hence on the biosynthetic capacity of cells.
authors.affiliation: Institute of Biomedical and Life Sciences, Division of Biochemistry and Molecular Biology, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
authors.forename: Torsten
authors.initials: T
authors.lastname: Stein
authors.forename: Diane
authors.initials: D
authors.lastname: Crighton
authors.forename: John M
authors.initials: JM
authors.lastname: Boyle
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Varley
authors.forename: Robert J
authors.initials: RJ
authors.lastname: White
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001859:Bone Neoplasms / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D012516:Osteosarcoma / Q000473:pathology; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D012320:RNA Polymerase III / Q000378:metabolism*; D012356:RNA, Transfer, Leu / Q000235:genetics; D012097:Repressor Proteins; D014158:Transcription, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D012356:RNA, Transfer, Leu; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D012320:RNA Polymerase III