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Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein
Michael T Tetzlaff1, Wei Yu, Mamie Li
1Department of Human and Molecular Genetics, Texas Children's Hospital, Houston, TX 77030, USA.
Abstract:
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.
Insights
The Fbw7 protein is crucial for controlling cell signaling pathways. Its absence in mice leads to developmental defects and uncontrolled cell growth, highlighting its role as a tumor suppressor.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cancer Research
Background:
- F-box protein Fbw7 and its C. elegans homolog Sel-10 regulate ubiquitin-mediated protein turnover.
- Fbw7 targets cyclin E and Notch/Lin-12 transcriptional activators, which are implicated in tumorigenesis when dysregulated.
- Inactivating mutations in human Fbw7 suggest its role as a tumor suppressor.
Purpose of the Study:
- To create an in vivo mouse model to study the effects of Fbw7 deficiency.
- To investigate the consequences of dysregulated cyclin E and Notch signaling in the absence of Fbw7.
Main Methods:
- Generation of Fbw7-null mice.
- Analysis of developmental phenotypes, protein levels, and downstream signaling pathways in Fbw7-deficient embryos.
Main Results:
- Fbw7-null mice exhibit embryonic lethality around 10.5 days post coitus.
- Deficiencies observed in hematopoietic, vascular, and heart development.
- Elevated levels of cyclin E and Notch 1/4 intracellular domains were detected.
- Inappropriate DNA replication in placental giant trophoblast cells and activation of Hes1, Herp1, and Herp2 pathways were observed.
Conclusions:
- Fbw7 plays an essential role in mouse development by controlling cyclin E and Notch signaling.
- Fbw7 acts as a critical regulator of cell proliferation and differentiation.
- The findings support the role of Fbw7 as a tumor suppressor, essential for preventing uncontrolled cell growth.
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