Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis

doi:10.1073/pnas.1733908100

Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis

Department of Medical Oncology, Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115

Communicated by David M. Livingston, Dana–Farber Cancer Institute, Boston, MA, June 24, 2003 (received for review April 18, 2003)

Abstract

Cul1, a member of the cullin ubiquitin ligase family, forms a multiprotein complex known as SCF and plays an essential role in numerous cellular and biological activities. A Cul1 homologue, p185 (Cul7), has been isolated as an simian virus 40 large T antigen-binding protein. To understand the physiological role of p185, we generated mice lacking p185. p185 ^– ^/ ^– embryos are runted and die immediately after birth because of respiratory distress. Dermal and hypodermal hemorrhage is detected in mutant embryos at late gestational stage. p185 ^– ^/ ^– placentas show defects in the differentiation of the trophoblast lineage with an abnormal vascular structure. We demonstrate that p185 forms an SCF-like complex with Skp1, Rbx1, Fbw6 (Fbx29), and FAP68 (FAP48, glomulin). FAP68 has recently been identified as a gene responsible for familial glomuvenous malformation. These results suggest that p185 forms a multiprotein complex and plays an important role in vascular morphogenesis.

Footnotes

↵ * To whom correspondence should be addressed. E-mail: james_decaprio{at}dfci.harvard.edu.
Abbreviations: SCF, Skp1–Cul1–F-box; MEFs, mouse embryonic fibroblasts; E4.5, E7.5, E10.5, E12.5, E16.5, and E18.5, embryonic day 4.5, 7.5, 10.5, 12.5, 16.5, and 18.5, respectively.