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Notch-dependent cell cycle arrest and apoptosis in mouse embryonic fibroblasts lacking Fbxw7

Y Ishikawa1, I Onoyama, K I Nakayama

  • 1Department of Developmental Genetics, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Japan.

Oncogene
|July 22, 2008
PubMed

Insights

The F-box protein Fbxw7 normally degrades Notch1 to promote cell survival and cell cycle progression. Loss of Fbxw7 causes Notch1 accumulation, leading to cell cycle arrest and apoptosis in mouse cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • F-box protein Fbxw7 targets cell cycle regulators like cyclin E and c-Myc for degradation.
  • Mutations in FBXW7 are found in human cancers, suggesting a tumor suppressor role.
  • The precise physiological function of Fbxw7 in normal cells is not fully understood.

Purpose of the Study:

  • To investigate the physiological role of Fbxw7 in mouse embryonic fibroblasts (MEFs).
  • To determine the impact of Fbxw7 loss on cell cycle progression and apoptosis.
  • To elucidate the downstream signaling pathways affected by Fbxw7 deficiency.

Main Methods:

  • Conditional ablation of Fbxw7 in MEFs.
  • Analysis of cell cycle progression and apoptosis.
  • Manipulation of Notch1 and RBP-J signaling pathways.
  • Assessment of p53's role in the observed phenotypes.

Main Results:

  • Fbxw7 deficiency in MEFs led to cell cycle arrest and apoptosis.
  • Abnormal accumulation of Notch1 intracellular domain (NICD1) was observed in Fbxw7-deficient cells.
  • Forced NICD1 expression mimicked the Fbxw7-deficient phenotype.
  • The phenotype was dependent on the Notch1-RBP-J pathway and partially dependent on p53.

Conclusions:

  • Fbxw7 promotes cell cycle progression and survival by degrading Notch1.
  • Loss of Fbxw7 function results in NICD1 accumulation, causing cell cycle arrest and apoptosis.
  • Fbxw7 may not function as a tumor suppressor in MEFs, contrary to previous implications.

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