Peng Fuwang, Dhillon Navneet K, Yao Honghong, Zhu Xuhui, Williams Rachel, Buch Shilpa
Department of Molecular & Integrative Physiology, 5000 Wahl Hall East, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
Eur J Neurosci. 2008 Oct;28(7):1255-64. doi: 10.1111/j.1460-9568.2008.06444.x.
Platelet-derived growth factor (PDGF) has been implicated in promoting survival and proliferation of immature neurons, and even protecting neurons from gp120-induced cytotoxicity. However, the mechanisms involved in neuroprotection are not well understood. In the present study we demonstrate the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in PDGF-mediated neuroprotection. Pharmacological inhibition of PI3K greatly reduced the ability of PDGF-BB to block gp120 IIIB-mediated apoptosis and cell death in human neuroblastoma cells. The role of Akt in PDGF-mediated protection was further corroborated using a dominant-negative mutant of Akt, which was able to block the protective effect of PDGF. We next sequentially examined the signals downstream of Akt in PDGF-mediated protection in human neuroblastoma cells. In cells pretreated with PDGF prior to gp120 there was increased phosphorylation of both GSK-3beta and Bad, an effect that was inhibited by PI3-kinase inhibitor. Nuclear translocation of NF-kappaB, which lies downstream of GSK-3beta, however, remained unaffected in cells treated with PDGF. In addition to inducing phosphorylation of Bad, PDGF-mediated protection also involved down-regulation of the proapoptotic protein Bax. Furthermore, PDGF-mediated protection also involved the inhibition of gp120-induced release of mitochondrial cytochrome C. Our findings thus underscore the roles of both PI3K/Akt and Bcl family pathways in PDGF-mediated neuroprotection.
血小板衍生生长因子（PDGF）被认为可促进未成熟神经元的存活和增殖，甚至能保护神经元免受gp120诱导的细胞毒性作用。然而，其神经保护作用的机制尚未完全明确。在本研究中，我们证明了磷脂酰肌醇3激酶（PI3K）/Akt信号通路在PDGF介导的神经保护中的作用。PI3K的药理学抑制作用显著降低了PDGF-BB阻断gp120 IIIB介导的人神经母细胞瘤细胞凋亡和细胞死亡的能力。使用Akt的显性负性突变体进一步证实了Akt在PDGF介导的保护作用中的作用，该突变体能够阻断PDGF的保护作用。接下来，我们依次研究了人神经母细胞瘤细胞中PDGF介导的保护作用中Akt下游的信号。在用gp120处理之前先用PDGF预处理的细胞中，GSK-3β和Bad的磷酸化均增加，这种作用被PI3激酶抑制剂所抑制。然而，位于GSK-3β下游的NF-κB的核转位在用PDGF处理的细胞中未受影响。除了诱导Bad的磷酸化外，PDGF介导的保护作用还涉及促凋亡蛋白Bax的下调。此外，PDGF介导的保护作用还涉及抑制gp120诱导的线粒体细胞色素C的释放。因此，我们的研究结果强调了PI3K/Akt和Bcl家族信号通路在PDGF介导的神经保护中的作用。
