RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome.

2.50
Hdl Handle:
http://hdl.handle.net/10541/84409
Title:
RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome.
Authors:
Stein, Torsten; Crighton, Diane; Boyle, John M; Varley, Jennifer; White, Robert J
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.
Affiliation:
Institute of Biomedical and Life Sciences, Division of Biochemistry and Molecular Biology, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
Citation:
RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome. 2002, 21 (19):2961-70 Oncogene
Journal:
Oncogene
Issue Date:
2-May-2002
URI:
http://hdl.handle.net/10541/84409
DOI:
10.1038/sj.onc.1205372
PubMed ID:
12082526
Type:
Article
Language:
en
ISSN:
0950-9232
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorStein, Torstenen
dc.contributor.authorCrighton, Dianeen
dc.contributor.authorBoyle, John Men
dc.contributor.authorVarley, Jenniferen
dc.contributor.authorWhite, Robert Jen
dc.date.accessioned2009-10-19T15:40:02Z-
dc.date.available2009-10-19T15:40:02Z-
dc.date.issued2002-05-02-
dc.identifier.citationRNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome. 2002, 21 (19):2961-70 Oncogeneen
dc.identifier.issn0950-9232-
dc.identifier.pmid12082526-
dc.identifier.doi10.1038/sj.onc.1205372-
dc.identifier.urihttp://hdl.handle.net/10541/84409-
dc.description.abstractRNA 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.en
dc.language.isoenen
dc.subjectBone Canceren
dc.subjectCancer Proteinsen
dc.subjectCultured Tumour Cellsen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAlleles-
dc.subject.meshAmino Acid Substitution-
dc.subject.meshBone Neoplasms-
dc.subject.meshFibroblasts-
dc.subject.meshGene Deletion-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshGenes, p53-
dc.subject.meshGerm-Line Mutation-
dc.subject.meshHumans-
dc.subject.meshLi-Fraumeni Syndrome-
dc.subject.meshNeoplasm Proteins-
dc.subject.meshNuclear Proteins-
dc.subject.meshOncogene Proteins, Viral-
dc.subject.meshOsteosarcoma-
dc.subject.meshPoint Mutation-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshProto-Oncogene Proteins c-mdm2-
dc.subject.meshRNA Polymerase III-
dc.subject.meshRNA, Transfer, Leu-
dc.subject.meshRepressor Proteins-
dc.subject.meshTranscription, Genetic-
dc.subject.meshTumor Cells, Cultured-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleRNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome.en
dc.typeArticleen
dc.contributor.departmentInstitute of Biomedical and Life Sciences, Division of Biochemistry and Molecular Biology, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.en
dc.identifier.journalOncogeneen

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