Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α
Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α
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DOI：
10.1038/81715
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发表时间：
2000-11-01
期刊：
影响因子：
30.8
通讯作者：
Cantley, LC
中科院分区：
文献类型：
--
作者：
Fruman, DA;Mauvais-Jarvis, F;Cantley, LC
磷酸肌醇 3-激酶产生 3'-磷酸化磷酸肌醇，作为第二信使将其他信号蛋白招募到膜上 (1)。 Pi3ks 可由许多细胞外刺激激活，并与多种细胞反应有关(1)。 Pi3k基因家族很复杂，不同类别和亚型的生理作用尚不清楚。 Pik3r1 基因编码三种蛋白质（p85 α、p55 α 和 p50 α），它们作为 I-A Pi3ks 的调节亚基（参考文献 2）。仅缺乏 p85a 同工型的小鼠可以存活，但表现出低血糖和与 p55 α 和 p50 α 变体上调相关的胰岛素敏感性增加 (3)。在此，我们报告 Pik3r1 所有蛋白质产物的丢失会导致围产期死亡。除其他异常外，我们观察到广泛的肝细胞坏死和乳糜性腹水，我们还注意到骨骼肌纤维增大、棕色脂肪坏死和心脏组织钙化。在肝脏和肌肉中，主要调节亚型的缺失导致 I-A 类 Pi3k 催化亚基的表达和活性大幅下降：尽管如此，纯合子小鼠仍然表现出低血糖、较低的胰岛素水平和增加的葡萄糖耐量。我们的研究结果表明，在缺乏 p85 α 的小鼠中，p55 α 和/或 p50 α 是生存所必需的，但不是低血糖发生所必需的。
Phosphoinositide 3-kinases produce 3'-phosphorylated phosphoinositides that act as second messengers to recruit other signalling proteins to the membrane(1). Pi3ks are activated by many extracellular stimuli and have been implicated in a variety of cellular responses(1). The Pi3k gene family is complex and the physiological roles of different classes and isoforms are not clear. The gene Pik3r1 encodes three proteins (p85 alpha, p55 alpha and p50 alpha) that serve as regulatory subunits of class I-A Pi3ks (ref. 2). Mice lacking only the p85a isoform are viable but display hypoglycaemia and increased insulin sensitivity correlating with upregulation of the p55 alpha and p50 alpha variants(3). Here we report that loss of all protein products of Pik3r1 results in perinatal lethality. We observed, among other abnormalities, extensive hepatocyte necrosis and chylous ascites, We also noted enlarged skeletal muscle fibres, brown fat necrosis and calcification of cardiac tissue. In liver and muscle, loss of the major regulatory isoform caused a great decrease in expression and activity of class I-A Pi3k catalytic subunits: nevertheless, homozygous mice still displayed hypoglycaemia, lower insulin levels and increased glucose tolerance. Our findings reveal that p55 alpha and/or p50 alpha are required for survival, but not for development of hypoglycaemia, in mice lacking p85 alpha.