mTORC1 promotes survival through translational control of Mcl-1.
Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is a frequent occurrence in human cancers and a major promoter of chemotherapeutic resistance. Inhibition of one downstream target in this pathway, mTORC1, has shown potential to improve chemosensitivity. However, the mechanisms and genetic modifications that confer sensitivity to mTORC1 inhibitors remain unclear. Here, we demonstrate that loss of TSC2 in the E mu-myc murine lymphoma model leads to mTORC1 activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation. Tumors from Tsc2(+/-)E mu-Myc mice underwent rapid apoptosis upon blockade of mTORC1 by rapamycin. We identified myeloid cell leukemia sequence 1 (Mcl-1), a bcl-2 like family member, as a translationally regulated genetic determinant of mTORC1-dependent survival. Our results indicate that the extent by which rapamycin can modulate expression of Mcl-1 is an important feature of the rapamycin response.
Mills
John R
JR
Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6.
Hippo
Yoshitaka
Y
Robert
Francis
F
Chen
Samuel M H
SM
Malina
Abba
A
Lin
Chen-Ju
CJ
Trojahn
Ulrike
U
Wendel
Hans-Guido
HG
Charest
Al
A
Bronson
Roderick T
RT
Kogan
Scott C
SC
Nadon
Robert
R
Housman
David E
DE
Lowe
Scott W
SW
Pelletier
Jerry
J
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008223:Lymphoma / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus