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Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
Open Life Sciences ( IF 1.7 ) Pub Date : 2015-01-19 , DOI: 10.1515/biol-2015-0048
Mee Rie Sheen 1 , Sandra L Warner 2 , Jennifer L Fields 2 , Jose R Conejo-Garcia 3 , Steven Fiering 4
Affiliation  

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.

中文翻译:


肉豆蔻酰化 p110α 因发育和血管缺陷导致胚胎死亡



摘要 磷脂酰肌醇 3 激酶 (PI3K) 信号通路调节许多重要的细胞功能。 PIK3CA 基因编码 PI3K 的 p110α 催化亚基,其功能失调的影响已通过一系列人类癌症中频繁获得的功能突变得到验证。我们生成了具有诱导型 PI3K 组成型活性形式的小鼠模型。在此模型中,Cre 重组酶激活 p110α 肉豆蔻酰化形式 (myr-p110α) 的表达。 p110α 的肉豆蔻酰化版本将蛋白质带到细胞膜的细胞质侧,模拟 p110α 催化亚基的正常激活机制并激活 PI3K 酶。在发育中的小鼠的所有细胞中,由 myr-p110α 诱导的组成型激活的 PI3K 信号传导导致胚胎发育过程中的致死性。转基因Cre;myr-p110α杂合胚胎表现出形态畸形和血管发育不良,胚胎和胚外卵黄囊血管极度扩张和出血。先前的研究表明,胚胎发育过程中 p110α 的丢失会导致血管生成破坏,在这里我们表明,在发育过程中通过功能突变获得的 p110α 的组成性激活也会以类似的方式破坏血管生成/血管生成。这些发现证明了在胚胎血管生成/血管生成过程中严格调节 PI3K 信号传导的重要性。
更新日期:2015-01-19
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