Hypergrowth mTORC1 Signals Translationally Activate the ARF Tumor Suppressor Checkpoint

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.

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ACKNOWLEDGMENTS

We thank all the members of the Weber lab for their comments and technical assistance. We also thank David Kwiatkowski and Jeffrey Arbeit for the Tsc1^flox/flox mice, Robert Weinberg for the pWZL-GFP-IRES-blast and pWZL-Ras^V12-IRES-blast constructs, and Martine Roussel for the pBabe-puro-Ras^V12 construct. We are very grateful to David Beebe, Jeffrey Arbeit, Ron Bose, and Fanxin Long for insightful discussions.

A.P.M. was supported by Department of Defense Breast Cancer Research Program award X81XWH-08-BCRP-PREDOC. A.J.S. was supported by Komen for the Cure grant KG091234. This work was supported by NIH grant CA120436 and an Era of Hope Scholar Award in Breast Cancer Research (BC007304) to J.D.W.

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