title: The ARF tumor-suppressor controls Drosha translation to prevent Ras-driven transformation.
abstract: ARF is a multifunctional tumor suppressor that acts as both a sensor of oncogenic stimuli and as a key regulator of ribosome biogenesis. Recently, our group established the DEAD-box RNA helicase and microRNA (miRNA) microprocessor accessory subunit, DDX5, as a critical target of basal ARF function. To identify other molecular targets of ARF, we focused on known interacting proteins of DDX5 in the microprocessor complex. Drosha, the catalytic core of the microprocessor complex, has a critical role in the maturation of specific non-coding RNAs, including miRNAs and ribosomal RNAs (rRNAs). Here, we report that chronic or acute loss of Arf enhanced Drosha protein expression. This induction did not involve Drosha mRNA transcription or protein stability but rather relied on the increased translation of existing Drosha mRNAs. Enhanced Drosha expression did not alter global miRNA production but rather modified expression of a subset of miRNAs in the absence of Arf. Elevated Drosha protein levels were required to maintain the increased rRNA synthesis and cellular proliferation observed in the absence of Arf. Arf-deficient cells transformed by oncogenic Ras(V12) were dependent on increased Drosha expression as Drosha knockdown was sufficient to inhibit Ras-dependent cellular transformation. Thus, we propose that ARF regulates Drosha mRNA translation to prevent aberrant cell proliferation and Ras-dependent transformation.
authors: 1] BRIGHT Institute, Washington University School of Medicine, St Louis, MO, USA [2] Department of Internal Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors: M J
authors: MJ
authors: Kuchenreuther
authors: 1] BRIGHT Institute, Washington University School of Medicine, St Louis, MO, USA [2] Department of Internal Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO, USA [3] Department of Cell Biology, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.
authors: J D
authors: JD
authors: Weber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D014176:Protein Biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs; D012333:RNA, Messenger; D012335:RNA, Ribosomal; C513400:Drosha protein, mouse; D043244:Ribonuclease III; D018631:ras Proteins