Journal
CANCER CELL
Volume 17, Issue 3, Pages 249-261Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2010.01.021
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Funding
- Intellikine, Inc.
- V Foundation for Cancer Research
- National Cancer Institute [CA77429]
- National Institutes of Health
- UCSF Prostate Cancer SPORE Career Development Program
- American Italian Cancer Foundation
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We genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. The therapeutic benefit of PP242 is mediated through inhibition of mTORC1-dependent 4EBP-eIF4E hyperactivation. Thus, the 4EBP-eIF4E axis downstream of mTOR is a druggable mediator of translational control and Akt-mediated tumorigenesis that has important implications for the treatment of human cancers.
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