Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 10, Pages 3338-3345Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0307875101
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Funding
- NCI NIH HHS [CA58024] Funding Source: Medline
- NHLBI NIH HHS [P01 HL049953, P01-HL49953] Funding Source: Medline
- NIA NIH HHS [R01 AG011085, AG11085] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007696, R01 DK057693, T32DK07696, DK57693] Funding Source: Medline
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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.
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