Kennedy S G, Wagner A J, Conzen S D, Jordán J, Bellacosa A, Tsichlis P N, Hay N
The Ben May Institute for Cancer Research and Department of Pharmacological and Physiological Sciences, The University of Chicago, Illinois 60637, USA.
Genes Dev. 1997 Mar 15;11(6):701-13. doi: 10.1101/gad.11.6.701.
Serum and certain growth factors have the ability to inhibit programmed cell death (apoptosis) and promote survival. The mechanism by which growth factors deliver an anti-apoptotic signal and the mechanism by which this survival signal is uncoupled from mitogenesis are not clear. We studied five downstream effectors of growth factor receptors--Ras, Raf, Src, phosphoinositide 3-kinase (PI 3-kinase), and Akt (PKB)--for their abilities to block apoptosis. Activated forms of Ras, Raf, and Src, although transforming, were not sufficient to deliver a survival signal upon serum withdrawal. In contrast, inhibition of PI 3-kinase accelerated apoptosis, and an activated form of the serine/threonine kinase Akt, a downstream effector of PI 3-kinase, blocked apoptosis. The ability of Akt to promote survival was dependent on and proportional to its kinase activity. In Rat1a fibroblasts, activated Akt did not alter Bcl-2 or Bcl-X(L) expression but inhibited Ced3/ICE-like activity. Thus, the PI 3-kinase/Akt (PKB) signaling pathway transduces a survival signal that ultimately blocks Ced3/ICE-like activity. These results suggest that uncoupling of survival and mitogenesis can be explained by differing abilities of distinct mitogens to efficiently induce the PI 3-kinase/Akt signaling pathway.
血清和某些生长因子具有抑制程序性细胞死亡（凋亡）并促进细胞存活的能力。生长因子传递抗凋亡信号的机制以及这种存活信号与有丝分裂原激活作用解偶联的机制尚不清楚。我们研究了生长因子受体的五种下游效应分子——Ras、Raf、Src、磷酸肌醇3激酶（PI 3激酶）和Akt（蛋白激酶B）——阻断凋亡的能力。Ras、Raf和Src的激活形式虽然具有转化作用，但在血清撤除后不足以传递存活信号。相反，抑制PI 3激酶会加速凋亡，而作为PI 3激酶下游效应分子的丝氨酸/苏氨酸激酶Akt的激活形式则能阻断凋亡。Akt促进存活的能力取决于其激酶活性并与之成比例。在大鼠1a成纤维细胞中，激活的Akt不会改变Bcl-2或Bcl-X(L)的表达，但会抑制Ced3/ICE样活性。因此，PI 3激酶/Akt（蛋白激酶B）信号通路转导一种最终阻断Ced3/ICE样活性的存活信号。这些结果表明，存活与有丝分裂原激活作用的解偶联可以通过不同的有丝分裂原有效诱导PI 3激酶/Akt信号通路的不同能力来解释。
