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(A), I(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(A) kinase isozymes are heterodimers that are active at 37°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 α isoform of the 110-kDa catalytic subunit (Pik3ca) of the α isozyme of the type I(A) kinases, leading to loss of expression of the p110 catalytic subunit. We show that Pik3ca(del/del) embryos are developmentally delayed at embryonic day (E) 9.5 and die between E9.5 and E10.5. E9.5 Pik3ca(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(del/del) embryos fail to replicate in Dulbecco's modified Eagle's medium and fetal calf serum, even with supplemental growth factors.
CITATION STYLE
Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A., & Nussbaum, R. L. (1999). Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase. Journal of Biological Chemistry, 274(16), 10963–10968. https://doi.org/10.1074/jbc.274.16.10963
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