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Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects

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...

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Autores principales: Sheen, Mee Rie, Warner, Sandra L., Fields, Jennifer L., Conejo-Garcia, Jose R., Fiering, Steven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966669/
https://www.ncbi.nlm.nih.gov/pubmed/27482546
http://dx.doi.org/10.1515/biol-2015-0048
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author Sheen, Mee Rie
Warner, Sandra L.
Fields, Jennifer L.
Conejo-Garcia, Jose R.
Fiering, Steven
author_facet Sheen, Mee Rie
Warner, Sandra L.
Fields, Jennifer L.
Conejo-Garcia, Jose R.
Fiering, Steven
author_sort Sheen, Mee Rie
collection PubMed
description 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..
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spelling pubmed-49666692016-10-01 Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects Sheen, Mee Rie Warner, Sandra L. Fields, Jennifer L. Conejo-Garcia, Jose R. Fiering, Steven Open Life Sci Article 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.. 2015-10-19 2015-10 /pmc/articles/PMC4966669/ /pubmed/27482546 http://dx.doi.org/10.1515/biol-2015-0048 Text en http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
spellingShingle Article
Sheen, Mee Rie
Warner, Sandra L.
Fields, Jennifer L.
Conejo-Garcia, Jose R.
Fiering, Steven
Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
title Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
title_full Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
title_fullStr Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
title_full_unstemmed Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
title_short Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
title_sort myristoylated p110α causes embryonic death due to developmental and vascular defects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966669/
https://www.ncbi.nlm.nih.gov/pubmed/27482546
http://dx.doi.org/10.1515/biol-2015-0048
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