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Open Life Sci. 2015 Oct;10(1):461-478. Epub 2015 Oct 19.

Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects.

Author information

1
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States.
2
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States; Norris Cotton Cancer Center, Lebanon, NH 03756, United States.
3
umor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, United States.
4
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States.

Abstract

The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating the PIK3CA gene, encoding the p110α catalytic subunit of PI3K, is validated by frequent gain of function mutations in a range of human cancers. We generated a mouse model with an inducible constitutively active form of PI3K. In this model Cre recombinase activates expression of a myristoylated form of p110α (myr-p110α). The myristoylated version of p110α brings the protein to the cytoplasmic side of the cell membrane, which mimics the normal activation mechanism for the p110α catalytic subunit and activates the PI3K enzyme. Constitutively activated PI3K signaling induced by myr-p110α in all cells of the developing mouse caused lethality during embryonic development. Transgenic Cre;myr-p110α heterozygous embryos displayed morphological malformation and poor vascular development with extremely dilated blood vessels and hemorrhage in the embryo and the extraembryonic yolk sac. Previous studies demonstrated that loss of p110α during embryonic development causes angiogenic disruption and here we show that constitutive activation of p110α by gain of function mutation during development also disrupts vasculogenesis/angiogenesis in what appears to be a similar manner. These finding demonstrate the importance of tight regulation of PI3K signaling during embryonic vasculogenesis/angiogenesis..

KEYWORDS:

Cre recombinase; PIK3CA; angiogenesis; embryonic development; hemorrhage; lethality; morphological malformation; myristoylated; p110α; vasculogenesis

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