mTORC1 promotes survival through translational control of Mcl-1

Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10853-8. doi: 10.1073/pnas.0804821105. Epub 2008 Jul 29.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Immunoblotting
  • Immunoprecipitation
  • Lymphoma / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Sirolimus / metabolism*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • MCL1 protein, human
  • Mcl1 protein, mouse
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TSC2 protein, human
  • Transcription Factors
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus