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.
MeSH terms
-
Animals
-
Breast Neoplasms / drug therapy
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism*
-
Breast Neoplasms / pathology
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism*
-
Cell Line
-
Cell Line, Tumor
-
F-Box Proteins / genetics
-
F-Box Proteins / metabolism*
-
F-Box-WD Repeat-Containing Protein 7
-
Gene Deletion
-
Gene Dosage
-
Gene Silencing
-
Genes, Tumor Suppressor
-
Humans
-
Mice
-
Mice, Nude
-
Mutation
-
Neoplasm Transplantation
-
PTEN Phosphohydrolase / genetics
-
PTEN Phosphohydrolase / metabolism*
-
Phosphorylation
-
Protein Binding
-
Protein Kinases / metabolism*
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction
-
Sirolimus / pharmacology
-
Sirolimus / therapeutic use
-
TOR Serine-Threonine Kinases
-
Transfection
-
Tumor Suppressor Proteins / metabolism*
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism*
-
Ubiquitination
Substances
-
Cell Cycle Proteins
-
F-Box Proteins
-
F-Box-WD Repeat-Containing Protein 7
-
FBXW7 protein, human
-
Tumor Suppressor Proteins
-
Ubiquitin-Protein Ligases
-
Protein Kinases
-
MTOR protein, human
-
mTOR protein, mouse
-
Proto-Oncogene Proteins c-akt
-
TOR Serine-Threonine Kinases
-
PTEN Phosphohydrolase
-
PTEN protein, human
-
Sirolimus