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

• Published in: Science (American Association for the Advancement of Science) Vol. 321; no. 5895; pp. 1499 - 1502
• Main Authors: Mao, Jian-Hua, Kim, Il-Jin, Wu, Di, Climent, Joan, Kang, Hio Chung, DelRosario, Reyno, Balmain, Allan
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 12.09.2008; The American Association for the Advancement of Science
• Subjects: Animals; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cell Line, Tumor; Cell lines; Cellular biology; Cellular immunity; Enzymes; F-Box Proteins - genetics; F-Box Proteins - metabolism; F-Box-WD Repeat-Containing Protein 7; Gene Deletion; Gene Dosage; Gene expression regulation; Gene Silencing; Genes, Tumor Suppressor; Genetic mutation; Gynecology. Andrology. Obstetrics; HCT116 cells; Humans; Immunoprecipitation; Mammary gland diseases; Medical sciences; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; Phosphorylation; Protein Binding; Protein Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Signal Transduction; Sirolimus - pharmacology; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases; Transfection; Tumor cell line; Tumor Suppressor Proteins - metabolism; Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Human; Breast disease; Targeting; Breast cancer; Malignant tumor; Degradation; Posttranslational modification; Mammary gland diseases; Ubiquitination; Cancerology; Mammalian target of rapamycin; Genetics; PTEN Gene; Cancer; Tumor suppressor gene; Primary cancer
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1162981

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.