Proc Natl Acad Sci U S A 2008,
Mills, John R; Hippo, Yoshitaka; Robert, Francis; Chen, Samuel M H; Malina, Abba; Lin, Chen-Ju; Trojahn, Ulrike; Wendel, Hans-Guido; Charest, Al; Bronson, Roderick T; Kogan, Scott C; Nadon, Robert; Housman, David E; Lowe, Scott W; Pelletier, Jerry
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.
Diseases/Pathways annotated by Medline MESH:
Document information provided by NCBI PubMed
Text Mining Data
mTORC1 ⊣ TSC2: " Here, we demonstrate that loss of TSC2
in the E mu-myc murine lymphoma model leads
activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation "
Manually curated Databases
No curated data.