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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.

Pubmed ID: 16790550

Authors

  • Yeh JR
  • Ju R
  • Brdlik CM
  • Zhang W
  • Zhang Y
  • Matyskiela ME
  • Shotwell JD
  • Crews CM

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 5, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: CA083049
  • Agency: NCI NIH HHS, Id: R01 CA083049
  • Agency: NCI NIH HHS, Id: R01 CA083049-08

Mesh Terms

  • 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