SCF(FBW7) Regulates Cellular Apoptosis by Targeting MCL1 for Ubiquitylation and Destruction

Nature. 2011 Mar 3;471(7336):104-9. doi: 10.1038/nature09732.

Abstract

The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis* / drug effects
  • Benzenesulfonates / pharmacology
  • Biphenyl Compounds / pharmacology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Mice
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Niacinamide / analogs & derivatives
  • Nitrophenols / pharmacology
  • Phenylurea Compounds
  • Phosphorylation
  • Piperazines / pharmacology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / chemistry*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Pyridines / pharmacology
  • SKP Cullin F-Box Protein Ligases / chemistry*
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Sorafenib
  • Sulfonamides / pharmacology
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination* / drug effects

Substances

  • ABT-737
  • Benzenesulfonates
  • Biphenyl Compounds
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Fbxw7 protein, mouse
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols
  • Phenylurea Compounds
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • Sulfonamides
  • Tumor Suppressor Proteins
  • Niacinamide
  • Sorafenib
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases
  • Glycogen Synthase Kinase 3