title: P19ARF and RasV¹² offer opposing regulation of DHX33 translation to dictate tumor cell fate.
abstract: DHX33 is a pivotal DEAH-box RNA helicase in the multistep process of RNA polymerase I-directed transcription of the ribosomal DNA locus. We explored the regulation of DHX33 expression by Ras(V12) and ARF to determine DHX33's role in sensing these opposing signals to regulate ribosome biogenesis. In wild-type primary fibroblasts, Ras(V12) infection induced a transient increase in DHX33 protein level, as well as an rRNA transcriptional rate that was eventually suppressed by a delayed activation of the ARF/p53 pathway. DHX33 expression was exclusively controlled at the level of translation. ARF caused a dramatic reduction in polysome-associated DHX33 mRNAs, while Ras(V12) led to a complete shift of existing DHX33 mRNAs to actively translating polysomes. The translation of DHX33 by Ras(V12) was sensitive to inhibitors of phosphatidylinositol 3-kinase, mTOR, and mitogen-activated protein and was pivotal for enhanced rRNA transcription and enhanced overall cellular protein translation. In addition, DHX33 knockdown abolished Ras(V12)-induced rRNA transcription and protein translation and prevented both the in vitro and in vivo transforming properties of oncogenic Ras(V12). Our results directly implicate DHX33 as a crucial player in establishing rRNA synthesis rates in the face of Ras(V12) or ARF signals, adjusting ribosome biogenesis to match the appropriate growth or antigrowth signals.
authors: BRIGHT Institute and Department of Internal Medicine, Division of Molecular Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Yandong
authors: Y
authors: Zhang
authors: Anthony J
authors: AJ
authors: Saporita
authors: Jason D
authors: JD
authors: Weber
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014176:Protein Biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012318:RNA Polymerase I / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics; D034741:RNA, Small Interfering; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002070:Butadienes; C417743:Cdkn2a protein, mouse; D002867:Chromones; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009025:Morpholines; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D012318:RNA Polymerase I; C568925:DHX33 protein, human; C581514:DHX33 protein, mouse; D053487:DEAD-box RNA Helicases; D018631:ras Proteins
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