title: RNA helicase DDX5 is a p53-independent target of ARF that participates in ribosome biogenesis.
abstract: The p19ARF tumor suppressor limits ribosome biogenesis and responds to hyperproliferative signals to activate the p53 checkpoint response. Although its activation of p53 has been well characterized, the role of ARF in restraining nucleolar ribosome production is poorly understood. Here we report the use of a mass spectroscopic analysis to identify protein changes within the nucleoli of Arf-deficient mouse cells. Through this approach, we discovered that ARF limited the nucleolar localization of the RNA helicase DDX5, which promotes the synthesis and maturation of rRNA, ultimately increasing ribosome output and proliferation. ARF inhibited the interaction between DDX5 and nucleophosmin (NPM), preventing association of DDX5 with the rDNA promoter and nuclear pre-ribosomes. In addition, Arf-deficient cells transformed by oncogenic RasV12 were addicted to DDX5, because reduction of DDX5 was sufficient to impair RasV12-driven colony formation in soft agar and tumor growth in mice. Taken together, our findings indicate that DDX5 is a key p53-independent target of the ARF tumor suppressor and is a novel non-oncogene participant in ribosome biogenesis.
authors.affiliation: BRIGHT Institute and Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Saporita
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Chang
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Winkeler
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Apicelli
authors.forename: Raleigh D
authors.initials: RD
authors.lastname: Kladney
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wang
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.forename: Loren S
authors.initials: LS
authors.lastname: Michel
authors.forename: Jason D
authors.initials: JD
authors.lastname: Weber
mesh_terms: D000818:Animals; D002455:Cell Division; D002466:Cell Nucleolus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000502:physiology*; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D015689:Oncogene Protein p21(ras) / Q000502:physiology; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D012323:RNA Processing, Post-Transcriptional; D012335:RNA, Ribosomal / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004275:DNA, Ribosomal; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases; D015689:Oncogene Protein p21(ras)