Mouse Fbw7/Sel-10/Cdc4 Is Required for Notch Degradation during Vascular Development

Ryosuke Tsunematsu, Keiko Nakayama, Yuichi Oike, Masaaki Nishiyama, Noriko Ishida, Shigetsugu Hatakeyama, Yasumasa Bessho, Ryoichiro Kageyama, Toshio Suda, Keiichi Nakayama

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197 Citations (Scopus)

Abstract

Mammalian Fbw7 (also known as Sel-10, hCdc4, or hAgo) is the F-box protein component of an SCF (Skp1-Cul1-F-box protein-Rbx1)-type ubiquitin ligase, and the mouse Fbw7 is expressed prominently in the endothelial cell lineage of embryos. We generated mice deficient in Fbw7 and found that the embryos died in utero at embryonic day 10.5-11.5, manifesting marked abnormalities in vascular development. Vascular remodeling was impaired in the brain and yolk sac, and the major trunk veins were not formed. In vitro para-aortic splanchnopleural explant cultures from Fbw7-/- embryos also manifested an impairment of vascular network formation. Notch4, which is the product of the proto-oncogene Int3 and an endothelial cell-specific mammalian isoform of Notch, accumulated in Fbw7-/- embryos, resulting in an increased expression of Hey1, which encodes a transcriptional repressor that acts downstream of Notch signaling and is implicated in vascular development. Expression of Notch1, -2, or -3 or of cyclin E was unaffected in Fbw 7-/- embryos. Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development.

Original languageEnglish
Pages (from-to)9417-9423
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number10
DOIs
Publication statusPublished - Mar 5 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tsunematsu, R., Nakayama, K., Oike, Y., Nishiyama, M., Ishida, N., Hatakeyama, S., Bessho, Y., Kageyama, R., Suda, T., & Nakayama, K. (2004). Mouse Fbw7/Sel-10/Cdc4 Is Required for Notch Degradation during Vascular Development. Journal of Biological Chemistry, 279(10), 9417-9423. https://doi.org/10.1074/jbc.M312337200