Targeted gene disruption of methionine aminopeptidase 2 results in an embryonic gastrulation defect and endothelial cell growth arrest.
Journal:
Proc. Natl. Acad. Sci. U.S.A. 2006 JulAuthors:
Yeh JR, Ju R, Brdlik CM, Zhang W, Zhang Y, Matyskiela ME, Shotwell JD, Crews CM
Abstract
The antiangiogenic agent fumagillin (Fg) and its analog TNP-470 bind to intracellular metalloprotease methionine aminopeptidase-2 (MetAP-2) and inhibit endothelial cell growth in a p53-dependent manner. To confirm the role of MetAP-2 in endothelial cell proliferation and to validate it as a physiological target for the Fg class of antiangiogenic agents, we have generated a conditional MetAP-2 knockout mouse. Ubiquitous deletion of the MetAP-2 gene (MAP2) resulted in an early gastrulation defect,
...[more] which is bypassed in double MetAP-2/p53 knockout embryos. Targeted deletion of MAP2 specifically in the hemangioblast lineage resulted in abnormal vascular development, and these embryos die at the midsomite stage. In addition, knockdown of MetAP-2 using small interfering RNA or homologous recombination specifically suppresses the proliferation of cultured endothelial cells. Together, these results demonstrate an essential role for MetAP-2 in angiogenesis and indicate that MetAP-2 is responsible for the endothelial cell growth arrest induced by Fg and its derivatives.[less]
Mesh Headings:
Aminopeptidases, Animals, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gastrula, Gene Expression Regulation, Developmental, Gene Expression Regulation, Enzymologic, Humans, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, RNA Interference, Time Factors, Tumor Suppressor Protein p53