Lawlor M A, Rotwein P
Molecular Medicine Division, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA.
Mol Cell Biol. 2000 Dec;20(23):8983-95. doi: 10.1128/MCB.20.23.8983-8995.2000.
Polypeptide growth factors activate specific transmembrane receptors, leading to the induction of multiple intracellular signal transduction pathways which control cell function and fate. Recent studies have shown that growth factors promote cell survival by stimulating the serine-threonine protein kinase Akt, which appears to function primarily as an antiapoptotic agent by inactivating death-promoting molecules. We previously established C2 muscle cell lines lacking endogenous expression of insulin-like growth factor II (IGF-II). These cells underwent apoptotic death in low-serum differentiation medium but could be maintained as viable myoblasts by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we show that IGF-I promotes muscle cell survival through Akt-mediated induction of the cyclin-dependent kinase inhibitor p21. Treatment of myoblasts with IGF-I or transfection with an inducible Akt maintained muscle cell survival and enhanced production of p21, and ectopic expression of p21 was able to sustain viability in the absence of growth factors. Blocking of p21 protein accumulation through a specific p21 antisense cDNA prevented survival regulated by IGF-I or Akt but did not block muscle cell viability mediated by PDGF-BB. Our results define Akt as an intermediate and p21 as a critical effector of an IGF-controlled myoblast survival pathway that is active during early myogenic differentiation and show that growth factors are able to maintain cell viability by inducing expression of pro-survival molecules.
多肽生长因子激活特定的跨膜受体，导致多种细胞内信号转导途径的诱导，这些途径控制细胞功能和命运。最近的研究表明，生长因子通过刺激丝氨酸 - 苏氨酸蛋白激酶Akt来促进细胞存活，Akt似乎主要通过使促死亡分子失活而作为一种抗凋亡因子发挥作用。我们先前建立了缺乏胰岛素样生长因子II（IGF-II）内源性表达的C2肌肉细胞系。这些细胞在低血清分化培养基中发生凋亡死亡，但可以通过激活IGF-I受体的IGF类似物或通过无关生长因子如血小板衍生生长因子BB（PDGF-BB）维持为存活的成肌细胞。在这里，我们表明IGF-I通过Akt介导的细胞周期蛋白依赖性激酶抑制剂p21的诱导来促进肌肉细胞存活。用IGF-I处理成肌细胞或用可诱导的Akt转染可维持肌肉细胞存活并增强p21的产生，并且p21的异位表达能够在没有生长因子的情况下维持细胞活力。通过特异性p21反义cDNA阻断p21蛋白积累可阻止由IGF-I或Akt调节的存活，但不阻断由PDGF-BB介导的肌肉细胞活力。我们的结果将Akt定义为中间分子，p21定义为IGF控制的成肌细胞存活途径的关键效应因子，该途径在早期肌源性分化过程中活跃，并表明生长因子能够通过诱导促存活分子的表达来维持细胞活力。
