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

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 Cull 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.