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FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression.

Science (New York, N.Y.) | Sep 12, 2008

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.

Pubmed ID: 18787170 RIS Download

Mesh terms: Animals | Breast Neoplasms | Cell Cycle Proteins | Cell Line | Cell Line, Tumor | F-Box Proteins | Gene Deletion | Gene Dosage | Gene Silencing | Genes, Tumor Suppressor | Humans | Mice | Mice, Nude | Mutation | Neoplasm Transplantation | PTEN Phosphohydrolase | Phosphorylation | Protein Binding | Protein Kinases | Proto-Oncogene Proteins c-akt | Signal Transduction | Sirolimus | TOR Serine-Threonine Kinases | Transfection | Tumor Suppressor Proteins | Ubiquitin-Protein Ligases | Ubiquitination

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Associated grants

  • Agency: NCI NIH HHS, Id: U01 CA084244-10
  • Agency: NCI NIH HHS, Id: R01 CA116481
  • Agency: NCI NIH HHS, Id: U01 CA084244-09
  • Agency: NCI NIH HHS, Id: U01 CA084244-08
  • Agency: NCI NIH HHS, Id: U01 CA084244

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