Format

Send to

Choose Destination
Mol Cell Biol. 2013 Apr;33(8):1594-607. doi: 10.1128/MCB.01220-12. Epub 2013 Feb 11.

P19ARF and RasV¹² offer opposing regulation of DHX33 translation to dictate tumor cell fate.

Author information

1
BRIGHT Institute and Department of Internal Medicine, Division of Molecular Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.

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.

PMID:
23401854
PMCID:
PMC3624250
DOI:
10.1128/MCB.01220-12
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center