MTORC1 Promotes Survival Through Translational Control of Mcl-1

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Jul 31

PMID 18664580

Citations 173

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

Affiliations

Soon will be listed here.

Abstract

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.

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