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Proliferative Defect and Embryonic Lethality in Mice Homozygous for a Deletion in the p110α Subunit of Phosphoinositide 3-Kinase

Phosphatidylinositol 3,4,5-trisphosphate is a phospholipid signaling molecule involved in many cellular functions including growth factor receptor signaling, cytoskeletal organization chemotaxis, apoptosis, and protein trafficking. Phosphorylation at the 3 position of the inositol ring is catalyzed...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-04, Vol.274 (16), p.10963-10968
Main Authors: Bi, Lei, Okabe, Ichiro, Bernard, David J., Wynshaw-Boris, Anthony, Nussbaum, Robert L.
Format: Article
Language:English
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Summary:Phosphatidylinositol 3,4,5-trisphosphate is a phospholipid signaling molecule involved in many cellular functions including growth factor receptor signaling, cytoskeletal organization chemotaxis, apoptosis, and protein trafficking. Phosphorylation at the 3 position of the inositol ring is catalyzed by many different 3-kinases (classified as types I sub(A), I sub(B) II, and III), but the physiological roles played by each of the different 3-kinase isozymes during embryonic development and in homeostasis in animals is incompletely understood. Mammalian type I sub(A) kinase isozymes are heterodimers that are active at 37 degree C when the catalytic 110-kDa subunit interacts through an amino-terminal binding domain with a regulatory 85- or 55-kDa subunit. Using gene targeting in embryonic stem cells, we deleted this binding domain in the gene encoding the alpha isoform of the 110-kDa catalytic subunit (Pik3ca) of the alpha isozyme of the type I sub(A) kinases, leading to loss of expression of the p110 catalytic subunit. We show that Pik3ca super(del/del) embryos are developmentally delayed at embryonic day (E) 9.5 and die between E9.5 and E10.5. E9.5 Pik3ca super(del/del) embryos have a profound proliferative defect but no increase in apoptosis. A proliferative defect is supported by the observation that fibroblasts from Pik3ca super(del/del) embryos fail to replicate in Dulbecco's modified Eagle's medium and fetal calf serum even with supplemental growth factors.
ISSN:0021-9258
DOI:10.1074/jbc.274.16.10963