Targeted gene disruption of methionine aminopeptidase 2 results in an embryonic gastrulation defect and endothelial cell growth arrest.
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, 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.
Yeh
Jing-Ruey J
JJ
Departments of *Molecular, Cell, and Developmental Biology.
Ju
Rong
R
Departments of *Molecular, Cell, and Developmental Biology.
Brdlik
Cathleen M
CM
Departments of *Molecular, Cell, and Developmental Biology.
Zhang
Wenjun
W
Departments of *Molecular, Cell, and Developmental Biology.
Zhang
Yi
Y
Departments of *Molecular, Cell, and Developmental Biology.
Matyskiela
Mary E
ME
Departments of *Molecular, Cell, and Developmental Biology.
Shotwell
Joseph D
JD
Departments of *Molecular, Cell, and Developmental Biology.
Crews
Craig M
CM
Departments of *Molecular, Cell, and Developmental Biology, craig.crews@yale.edu.|Pharmacology, and.|Chemistry, Yale University, New Haven, CT 06520-8103.
D000626:Aminopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology*; D005775:Gastrula / Q000201:enzymology* / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D034622:RNA Interference; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases