Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.

Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1-FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to gamma-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL.

Pubmed ID: 17646408 RIS Download

Mesh terms: Amyloid Precursor Protein Secretases | Cell Cycle Proteins | F-Box Proteins | Gene Expression Regulation, Neoplastic | Genes, Tumor Suppressor | Humans | Leukemia, T-Cell | Microscopy, Fluorescence | Mutation | Precursor Cell Lymphoblastic Leukemia-Lymphoma | Protein Binding | Protein Structure, Tertiary | Proto-Oncogene Proteins c-myc | Receptor, Notch1 | Stem Cell Factor | Ubiquitin-Protein Ligases

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA105129
  • Agency: NCI NIH HHS, Id: R01 CA120196-02
  • Agency: NCI NIH HHS, Id: CA120196
  • Agency: NCI NIH HHS, Id: R01 CA120196
  • Agency: NCI NIH HHS, Id: R01CA105129

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.