Journal
SCIENCE
Volume 321, Issue 5895, Pages 1499-1502Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1162981
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Funding
- NCI [U01 CA84244]
- U. S. Department of Energy [DE-FG02-03ER63630]
- University of California at San Francisco Research-Evaluation Allocation Committee (REAC)
- Barbara Bass Bakar Chair of Cancer Genetics
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The enzyme mTOR ( mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN ( phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.
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