• Register
X
Forgot Password

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

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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

Authors

  • Thompson BJ
  • Buonamici S
  • Sulis ML
  • Palomero T
  • Vilimas T
  • Basso G
  • Ferrando A
  • Aifantis I

Journal

The Journal of experimental medicine

Publication Data

August 6, 2007

Associated Grants

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

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