TY - JOUR
T1 - Hypergrowth mTORC1 signals translationally activate the ARF tumor suppressor checkpoint
AU - Miceli, Alexander P.
AU - Saporita, Anthony J.
AU - Weber, Jason D.
PY - 2012/1
Y1 - 2012/1
N2 - The ARF tumor suppressor is a potent sensor of hyperproliferative cues emanating fromoncogenic 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 amechanismmediated by the Dmp1 transcription factor. How-ever, we now show that ARF protein is still induced in response to Ras V12 in the absence of Dmp1 through the enhanced transla-tion of existing ArfmRNAs. 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 translationalmecha-nism. Hyperactivation ofmTORC1 through Tsc1 loss resulted in a signicant 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 fromRas V12 in the absence of Dmp1 repressed anchorage-independent colony formation in soft agar and tumor burden in an allograftmodel. Taken together, our data demonstrate the ability of the ARF tumor suppressor to respond to hypergrowth stimuli to prevent unwarranted tumor formation.
AB - The ARF tumor suppressor is a potent sensor of hyperproliferative cues emanating fromoncogenic 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 amechanismmediated by the Dmp1 transcription factor. How-ever, we now show that ARF protein is still induced in response to Ras V12 in the absence of Dmp1 through the enhanced transla-tion of existing ArfmRNAs. 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 translationalmecha-nism. Hyperactivation ofmTORC1 through Tsc1 loss resulted in a signicant 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 fromRas V12 in the absence of Dmp1 repressed anchorage-independent colony formation in soft agar and tumor burden in an allograftmodel. Taken together, our data demonstrate the ability of the ARF tumor suppressor to respond to hypergrowth stimuli to prevent unwarranted tumor formation.
UR - http://www.scopus.com/inward/record.url?scp=84856800924&partnerID=8YFLogxK
U2 - 10.1128/MCB.06030-11
DO - 10.1128/MCB.06030-11
M3 - Article
C2 - 22064482
AN - SCOPUS:84856800924
SN - 0270-7306
VL - 32
SP - 348
EP - 364
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 2
ER -