Notch-dependent cell cycle arrest and apoptosis in mouse embryonic fibroblasts lacking Fbxw7.
The F-box protein Fbxw7 mediates the ubiquitylation and consequent degradation of proteins that regulate cell cycle progression, including cyclin E, c-Myc, c-Jun and Notch. Moreover, certain human cancer cell lines harbor loss-of-function mutations in FBXW7 that result in excessive accumulation of Fbxw7 substrates, implicating Fbxw7 in tumor suppression. To elucidate the physiological function of Fbxw7, we conditionally ablated Fbxw7 in mouse embryonic fibroblasts (MEFs). Unexpectedly, loss of Fbxw7 induced cell cycle arrest and apoptosis that were accompanied by abnormal accumulation of the intracellular domain of Notch1 (NICD1). Forced expression of NICD1 in wild-type MEFs recapitulated the phenotype of the Fbxw7-deficient (Fbxw7(Delta/Delta)) MEFs. Conversely, deletion of Rbpj normalized the phenotype of Fbxw7(Delta/Delta) MEFs, indicating that this phenotype is dependent on the Notch1-RBP-J signaling pathway. Deletion of the p53 gene prevented cell cycle arrest but not the induction of apoptosis in Fbxw7(Delta/Delta) cells. These observations suggest that Fbxw7 does not function as an oncosuppressor in MEFs. Instead, it promotes cell cycle progression and cell survival through degradation of Notch1, with loss of Fbxw7 resulting in NICD1 accumulation, cell cycle arrest and apoptosis.
Ishikawa
Y
Y
Department of Developmental Genetics, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Japan.
Onoyama
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I
Nakayama
K I
KI
Nakayama
K
K
D053829:Amyloid Precursor Protein Secretases / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D044783:F-Box Proteins / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005347:Fibroblasts / Q000166:cytology; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D051881:Receptor, Notch1 / Q000032:analysis / Q000502:physiology*; D051883:Receptor, Notch2 / Q000032:analysis / Q000502:physiology; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000032:analysis / Q000502:physiology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C499373:Notch3 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex