Defective Cardiovascular Development and Elevated Cyclin E and Notch Proteins in Mice Lacking the Fbw7 F-Box Protein

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-03, Vol.101 (10), p.3338-3345
• Main Authors: Tetzlaff, Michael T., Yu, Wei, Li, Mamie, Zhang, Pumin, Finegold, Milton, Mahon, Kathleen, Harper, J. Wade, Schwartz, Robert J., Elledge, Stephen J.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological Sciences; Blood vessels; Cardiovascular Abnormalities - embryology; Cardiovascular Abnormalities - genetics; Cardiovascular Abnormalities - metabolism; Cell lines; Cells; Cellular biology; Cyclin E - metabolism; Cyclins; DNA, Complementary - genetics; Embryos; Endothelial cells; F-box protein; F-Box Proteins - genetics; F-Box Proteins - metabolism; Fbw7 protein; Female; Fetal Death - genetics; Gene Expression Regulation, Developmental; Gene Targeting; Heart ventricles; Herp1 protein; Herp2 protein; Mammals; Membrane Proteins - genetics; Membrane Proteins - metabolism; Messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Notch 1 protein; Notch 4 protein; Placenta; Placenta - metabolism; Polymerase chain reaction; Pregnancy; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor, Notch1; Receptor, Notch4; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Notch; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Signal Transduction; Transcription Factors; Tumors; Yolk sac
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0307875101

The mammalian F-box protein Fbw7 and its Caenorhabditis elegans counterpart Sel-10 have been implicated in the ubiquitin-mediated turnover of cyclin E as well as the Notch/Lin-12 family of transcriptional activators. Both unregulated Notch and cyclin E promote tumorigenesis, and inactivating mutations in human Fbw7 suggest that it may be a tumor suppressor. To generate an in vivo system to assess the consequences of such unregulated signaling, we generated mice deficient for Fbw7. Fbw7-null mice die around 10.5 days post coitus because of a combination of deficiencies in hematopoietic and vascular development and heart chamber maturation. The absence of Fbw7 results in elevated levels of cyclin E, concurrent with inappropriate DNA replication in placental giant trophoblast cells. Moreover, the levels of both Notch 1 and Notch 4 intracellular domains were elevated, leading to stimulation of downstream transcriptional pathways involving Hes1, Herp1, and Herp2. These data suggest essential functions for Fbw7 in controlling cyclin E and Notch signaling pathways in the mouse.