mTORC1 promotes survival through translational control of Mcl-1

• DOI: 10.1073/pnas.0804821105
• Publication Date: 2008-07-30T03:24:28Z
• Authors: John R. Mills; Yoshitaka Hippo; Francis Robert; Samuel M. H. Chen; Abba Malina; Chen-Ju Lin; Ulrike Trojahn; Hans-Guido Wendel; Al Charest; Roderick T. Bronson; Scott C. Kogan; Robert Nadon; David E. Housman; Scott W. Lowe; Jerry Pelletier
• Keywords: TSC2

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is a frequent occurrence in human cancers and major promoter chemotherapeutic resistance. Inhibition one downstream target this pathway, mTORC1, has shown potential to improve chemosensitivity. However, mechanisms genetic modifications that confer sensitivity mTORC1 inhibitors remain unclear. Here, we demonstrate loss TSC2 E μ- myc murine lymphoma model leads activation accelerated oncogenesis caused by defective apoptotic program despite compromised AKT phosphorylation. Tumors from Tsc2 +/− Myc mice underwent rapid apoptosis upon blockade rapamycin. We identified myeloid cell leukemia sequence 1 ( Mcl-1 ), bcl-2 like family member, as translationally regulated determinant mTORC1-dependent survival. Our results indicate extent which rapamycin can modulate expression an important feature response.