Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein
| Autor: | Milton J. Finegold, Stephen J. Elledge, Kathleen A. Mahon, Michael T. Tetzlaff, Robert J. Schwartz, Mamie Li, Pumin Zhang, Wei Yu, J. Wade Harper |
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| Rok vydání: | 2004 |
| Předmět: |
DNA
Complementary Cyclin E Placenta Cyclin D Cardiovascular Abnormalities Cyclin A Notch signaling pathway Receptors Cell Surface Mice Pregnancy Proto-Oncogene Proteins Animals RNA Messenger Receptor Notch1 HES1 Receptor Notch4 Fetal Death Notch 1 Mice Knockout Multidisciplinary Base Sequence Receptors Notch biology F-Box Proteins Gene Expression Regulation Developmental Membrane Proteins Biological Sciences Mice Inbred C57BL Notch proteins Gene Targeting Cancer research biology.protein Female Cyclin A2 Signal Transduction Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 101:3338-3345 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0307875101 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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