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Mol Cell Biol. 2012 Jan;32(2):348-64. doi: 10.1128/MCB.06030-11. Epub 2011 Nov 7.

Hypergrowth mTORC1 signals translationally activate the ARF tumor suppressor checkpoint.

Author information

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

Abstract

The ARF tumor suppressor is a potent sensor of hyperproliferative cues emanating from oncogenic signaling. ARF responds to these cues by eliciting a cell cycle arrest, effectively abating the tumorigenic potential of these stimuli. Prior reports have demonstrated that oncogenic Ras(V12) signaling induces ARF through a mechanism mediated by the Dmp1 transcription factor. However, we now show that ARF protein is still induced in response to Ras(V12) in the absence of Dmp1 through the enhanced translation of existing Arf mRNAs. Here, we report that the progrowth Ras/tuberous sclerosis complex (TSC)/mTORC1 signaling pathway regulates ARF protein expression and triggers ARF-mediated tumor suppression through a novel translational mechanism. Hyperactivation of mTORC1 through Tsc1 loss resulted in a significant increase in ARF expression, activation of the p53 pathway, and a dramatic cell cycle arrest, which were completely reversed upon Arf deletion. ARF protein induced from Ras(V12) in the absence of Dmp1 repressed anchorage-independent colony formation in soft agar and tumor burden in an allograft model. Taken together, our data demonstrate the ability of the ARF tumor suppressor to respond to hypergrowth stimuli to prevent unwarranted tumor formation.

PMID:
22064482
PMCID:
PMC3255786
DOI:
10.1128/MCB.06030-11
[Indexed for MEDLINE]
Free PMC Article

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