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Science 321 (5895): 1499-1502

Copyright © 2008 by the American Association for the Advancement of Science

FBXW7 Targets mTOR for Degradation and Cooperates with PTEN in Tumor Suppression

Jian-Hua Mao,1* Il-Jin Kim,1* Di Wu,1 Joan Climent,1 Hio Chung Kang,1 Reyno DelRosario,1 Allan Balmain1,2{dagger}

Abstract: 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.

1 Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, CA 94143, USA.
2 Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA 94143, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: abalmain{at}cc.ucsf.edu

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