PMID- 16790550
OWN - NLM
STAT- MEDLINE
DCOM- 20060816
LR  - 20220321
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 27
DP  - 2006 Jul 5
TI  - Targeted gene disruption of methionine aminopeptidase 2 results in an embryonic 
      gastrulation defect and endothelial cell growth arrest.
PG  - 10379-10384
LID - 10.1073/pnas.0511313103 [doi]
AB  - 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.
FAU - Yeh, Jing-Ruey J
AU  - Yeh JJ
AD  - Departments of *Molecular, Cell, and Developmental Biology.
FAU - Ju, Rong
AU  - Ju R
AD  - Departments of *Molecular, Cell, and Developmental Biology.
FAU - Brdlik, Cathleen M
AU  - Brdlik CM
AD  - Departments of *Molecular, Cell, and Developmental Biology.
FAU - Zhang, Wenjun
AU  - Zhang W
AD  - Departments of *Molecular, Cell, and Developmental Biology.
FAU - Zhang, Yi
AU  - Zhang Y
AD  - Departments of *Molecular, Cell, and Developmental Biology.
FAU - Matyskiela, Mary E
AU  - Matyskiela ME
AD  - Departments of *Molecular, Cell, and Developmental Biology.
FAU - Shotwell, Joseph D
AU  - Shotwell JD
AD  - Departments of *Molecular, Cell, and Developmental Biology.
FAU - Crews, Craig M
AU  - Crews CM
AD  - Departments of *Molecular, Cell, and Developmental Biology, craig.crews@yale.edu.
AD  - Pharmacology, and.
AD  - Chemistry, Yale University, New Haven, CT 06520-8103.
LA  - eng
GR  - R01 CA083049/CA/NCI NIH HHS/United States
GR  - R01 CA083049-08/CA/NCI NIH HHS/United States
GR  - CA083049/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20060621
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 3.4.11.- (Aminopeptidases)
RN  - EC 3.4.11.18 (methionine aminopeptidase 2)
RN  - EC 3.4.24.- (Metalloendopeptidases)
SB  - IM
MH  - Aminopeptidases/*deficiency/genetics/*metabolism
MH  - Animals
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Endothelial Cells/*cytology/*enzymology
MH  - Gastrula/*enzymology/*pathology
MH  - Gene Expression Regulation, Developmental
MH  - Gene Expression Regulation, Enzymologic
MH  - Humans
MH  - Metalloendopeptidases/*deficiency/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phenotype
MH  - RNA Interference
MH  - Time Factors
MH  - Tumor Suppressor Protein p53/metabolism
PMC - PMC1480595
COIS- Conflict of interest statement: No conflicts declared.
EDAT- 2006/06/23 09:00
MHDA- 2006/08/17 09:00
PMCR- 2006/06/21
CRDT- 2006/06/23 09:00
PHST- 2006/06/23 09:00 [pubmed]
PHST- 2006/08/17 09:00 [medline]
PHST- 2006/06/23 09:00 [entrez]
PHST- 2006/06/21 00:00 [pmc-release]
AID - 0511313103 [pii]
AID - 2597 [pii]
AID - 10.1073/pnas.0511313103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10379-10384. doi: 
      10.1073/pnas.0511313103. Epub 2006 Jun 21.