title: Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation.
abstract: RNA polymerase (pol) III transcription, responsible for the synthesis of various stable RNAs, including 5 S rRNAs and tRNAs, is regulated by oncogenic proteins and tumor suppressors. Although it is well established that RNA pol III-dependent transcription is deregulated in transformed cells and malignant tumors, it has not been determined whether this represents a cause or consequence of these processes. We show that Rat1a fibroblasts undergoing oncogenic transformation by the TATA-binding protein or c-Myc display enhanced RNA pol III transcription. Decreased expression of the RNA pol III-specific transcription factor Brf1 prevented this increase in RNA pol III transcription. Although the overall proliferation rates of these cells remained unchanged, the ability of cells to grow in an anchorage-independent manner and form tumors in mice was markedly reduced. Although overexpression of Brf1 modestly stimulated RNA pol III transcription, expression of a phosphomimic, Brf1-T145D, more significantly induced transcription. However, these increases in transcription were not sufficient to promote cellular transformation. Together, these results demonstrate that enhanced RNA pol III transcription is essential for anchorage-independent growth and tumorigenesis and that these events can be uncoupled from effects on anchorage-dependent proliferation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Sandra A S
authors.initials: SA
authors.lastname: Johnson
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Johnson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012320:RNA Polymerase III / Q000235:genetics / Q000378:metabolism*; D012341:RNA, Ribosomal, 5S / Q000096:biosynthesis / Q000235:genetics; D012343:RNA, Transfer / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism*; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C441028:BRF1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012341:RNA, Ribosomal, 5S; D035381:TATA-Binding Protein Associated Factors; D035181:TATA-Box Binding Protein; D012343:RNA, Transfer; D012320:RNA Polymerase III