Role of PTEN/PI3K pathway in endothelial cells.
PTEN (phosphatase and tensin homologue deleted on chromosome 10) is an important tumour-suppressor gene that encodes a 3-phosphatase. The major substrate of PTEN is PIP(3) (phosphatidylinositol 3,4,5-trisphosphate) generated by the action of PI3Ks (phosphoinositide 3-kinases). Hereditary mutation of PTEN causes tumour-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of PTEN in mice. Heterozygous mutation of PTEN in endothelial cells enhances postnatal neovascularization, including tumour angiogenesis necessary for tumour growth. This observation suggests that Cowden disease patients are not only at risk for additional tumorigenic mutations due to complete loss of PTEN function, but may also experience accelerated growth of incipient tumours due to enhanced angiogenesis. Homozygous mutation of Pten in murine endothelial cells impairs cardiovascular morphogenesis and is embryonic lethal due to endothelial cell hyperproliferation and impaired vascular remodelling. Additional homozygous mutation of p85alpha, the regulatory subunit of class IA PI3Ks, or p110gamma, the catalytic subunit of the sole class IB PI3K, led to a partial rescue of all phenotypes in our PTEN-deficient mice. Thus inhibition of the PI3K pathway, including the targeting of PI3Kgamma, may be an attractive therapeutic strategy for the treatment of various malignancies.
Suzuki
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A
Department of Molecular Biology, Akita University School of Medicine, Akita, Japan. suzuki@med.akita-u.ac.jp
Hamada
K
K
Sasaki
T
T
Mak
T W
TW
Nakano
T
T
D000818:Animals; D002455:Cell Division; D002874:Chromosome Mapping; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase