The Ubiquitin Ligase Nedd4-1 Is Required for Heart Development and Is a Suppressor of Thrombospondin-1
2010 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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The Ubiquitin Ligase Nedd4-1 Is Required for Heart Development and Is a Suppressor of Thrombospondin-1
Fouladkou, F.; Lu, C.; Jiang, C.; Zhou, L.; She, Y.; Walls, J. R. & Kawabe, H. et al. (2010)
Journal of biological chemistry, 285(9) pp. 6770-6780. DOI: https://doi.org/10.1074/jbc.M109.082347
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- Authors
- Fouladkou, Fatemeh; Lu, Chen; Jiang, Chong; Zhou, Limei; She, Yimin; Walls, Jonathon R.; Kawabe, Hiroshi; Brose, Nils ; Henkelman, R. M.; Huang, Annie; Bruneau, Benoit G.; Rotin, Daniela
- Abstract
- Nedd4 (Nedd4-1) is a Hect domain E3 ubiquitin ligase that also contains a C2 domain and three WW domains. Despite numerous in vitro studies, its biological function in vivo is not well understood. Here we show that disruption of Nedd4-1 in mice (leaving Nedd4-2 intact) caused embryonic lethality at mid gestation, with pronounced heart defects (double-outlet right ventricle and atrioventricular cushion defects) and vasculature abnormalities. Quantitative mass spectrometry and immunoblot analyses of lysates from the wild type and knock-out mouse embryonic fibroblasts to identify Nedd4-1 in vivo targets revealed dramatically increased amounts of thrombospondin-1 (Tsp-1) in the knock-out mouse embryonic fibroblasts and embryos. Tsp-1 is an inhibitor of angiogenesis, and its elevated level was mediated primarily by enhanced transcription. Interestingly, the administration of aspirin (an inhibitor of Tsp-1) to the pregnant heterozygote mothers led to a reduction in Tsp-1 levels and a substantial rescue of the embryonic lethality. These results suggest that Nedd4-1 is a suppressor of Tsp1 and that increased levels of Tsp-1 in the Nedd4-1 knock-out mice may have contributed to the developmental defect observed in the embryos.
- Issue Date
- 2010
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Journal
- Journal of biological chemistry
- ISSN
- 0021-9258