RNA Helicase DDX5 Is a p53-Independent Target of ARF That Participates in Ribosome Biogenesis

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2011-11, Vol.71 (21), p.6708-6717
Main Authors: SAPORITA, Anthony J, CHANG, Hsiang-Chun, WINKELER, Crystal L, APICELLI, Anthony J, KLADNEY, Raleigh D, JIANBO WANG, REID TOWNSEND, R, MICHEL, Loren S, WEBER, Jason D
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Cell Division
Cell Nucleolus - metabolism
Cell Transformation, Neoplastic - genetics
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16 - deficiency
Cyclin-Dependent Kinase Inhibitor p16 - physiology
DEAD-box RNA Helicases - physiology
DNA, Ribosomal - genetics
DNA, Ribosomal - metabolism
Fibroblasts
Medical sciences
Mice
Mice, Knockout
Mice, Nude
Nuclear Proteins - metabolism
Oncogene Protein p21(ras) - physiology
Pharmacology. Drug treatments
Promoter Regions, Genetic
Protein Transport
Ribosomes - metabolism
RNA Processing, Post-Transcriptional
RNA, Ribosomal - metabolism
Tumor Stem Cell Assay
Tumor Suppressor Protein p53 - physiology
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-11-1472