Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein.

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.

• Authors: Michael T Tetzlaff, Wei Yu, Mamie Li, Pumin Zhang, Milton Finegold, Kathleen Mahon, J Wade Harper, Robert J Schwartz, Stephen J Elledge
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 10 Pg. 3338-45 (Mar 09 2004) ISSN: 0027-8424 [Print] United States
• PMID: 14766969 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cyclin E
• DNA, Complementary
• F-Box Proteins
• Membrane Proteins
• NOTCH4 protein, human
• Notch1 protein, mouse
• Proto-Oncogene Proteins
• RNA, Messenger
• Receptor, Notch1
• Receptor, Notch4
• Receptors, Cell Surface
• Receptors, Notch
• Transcription Factors

Topics

• Animals
• Base Sequence
• Cardiovascular Abnormalities (embryology, genetics, metabolism)
• Cyclin E (metabolism)
• DNA, Complementary (genetics)
• F-Box Proteins (genetics, metabolism)
• Female
• Fetal Death (genetics)
• Gene Expression Regulation, Developmental
• Gene Targeting
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Placenta (metabolism)
• Pregnancy
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptor, Notch1
• Receptor, Notch4
• Receptors, Cell Surface (genetics, metabolism)
• Receptors, Notch
• Signal Transduction
• Transcription Factors