Eves E M, Xiong W, Bellacosa A, Kennedy S G, Tsichlis P N, Rosner M R, Hay N
Ben May Institute for Cancer Research and Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois 60637, USA.
Mol Cell Biol. 1998 Apr;18(4):2143-52. doi: 10.1128/MCB.18.4.2143.
Phosphatidylinositol (PI) 3-kinase has been suggested to mediate cell survival. Consistent with this possibility, apoptosis of conditionally (simian virus 40 Tts) immortalized rat hippocampal H19-7 neuronal cells was increased in response to wortmannin, an inhibitor of PI 3-kinase. Downstream effectors of PI 3-kinase include Rac1, protein kinase C, and the serine-threonine kinase Akt (protein kinase B). Here, we show that activation of Akt is one mechanism by which PI 3-kinase can mediate survival of H19-7 cells during serum deprivation or differentiation. While ectopic expression of wild-type Akt (c-Akt) does not significantly enhance survival in H19-7 cells, expression of activated forms of Akt (v-Akt or myristoylated Akt) results in enhanced survival which can be comparable to that conferred by Bcl-2. Conversely, expression of a dominant-negative mutant of Akt accelerates cell death upon serum deprivation or differentiation. Finally, the results indicate that Akt can transduce a survival signal for differentiating neuronal cells through a mechanism that is independent of induction of Bcl-2 or Bcl-XL or inhibition of Jun kinase activity.
磷脂酰肌醇（PI）3激酶被认为可介导细胞存活。与这种可能性一致的是，在对PI 3激酶抑制剂渥曼青霉素的反应中，条件性（猿猴病毒40大T抗原）永生化大鼠海马H19-7神经元细胞的凋亡增加。PI 3激酶的下游效应器包括Rac1、蛋白激酶C和丝氨酸 - 苏氨酸激酶Akt（蛋白激酶B）。在此，我们表明Akt的激活是PI 3激酶在血清剥夺或分化过程中介导H19-7细胞存活的一种机制。虽然野生型Akt（c-Akt）的异位表达不会显著增强H19-7细胞的存活，但激活形式的Akt（v-Akt或肉豆蔻酰化Akt）的表达会导致存活增强，这与Bcl-2所赋予的存活增强相当。相反，Akt的显性负突变体的表达会加速血清剥夺或分化后的细胞死亡。最后，结果表明Akt可以通过一种独立于诱导Bcl-2或Bcl-XL或抑制Jun激酶活性的机制，为分化中的神经元细胞转导存活信号。
