Hetman M, Kanning K, Cavanaugh J E, Xia Z
Toxicology Program, Department of Environmental Health, the Graduate Program in Neurobiology and Behavior, the Graduate Program in Molecular and Cell Biology, University of Washington, Seattle, Washington 98195-7234, USA.
J Biol Chem. 1999 Aug 6;274(32):22569-80. doi: 10.1074/jbc.274.32.22569.
Apoptosis is a form of programmed cell death that plays a pivotal role during development and in the homeostasis of the adult nervous systems. However, mechanisms that regulate neuronal apoptosis are not well defined. Here, we report that brain-derived neurotrophic factor (BDNF) protects cortical neurons against apoptosis induced by camptothecin or serum deprivation and activates the extracellular-signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI 3-kinase) pathways. Using pharmacological agents and transient transfection with dominant interfering or constitutive active components of the ERK or the PI 3-kinase pathway, we demonstrate that the ERK pathway plays a major role in BDNF neuroprotection against camptothecin. Furthermore, ERK is activated in cortical neurons during camptothecin-induced apoptosis, and inhibition of ERK increases apoptosis. In contrast, the PI 3-kinase pathway is the dominant survival mechanism for serum-dependent survival under normal culture conditions and for BDNF protection against serum withdrawal. These results suggest that the ERK pathway is one of several neuroprotective mechanisms that are activated by stress to counteract death signals in central nervous system neurons. Furthermore, the relative contribution of the ERK and PI 3-kinase pathways to neuronal survival may depend on the type of cellular injury.
细胞凋亡是一种程序性细胞死亡形式，在发育过程以及成体神经系统的稳态维持中发挥着关键作用。然而，调控神经元凋亡的机制尚未完全明确。在此，我们报告脑源性神经营养因子（BDNF）可保护皮质神经元免受喜树碱或血清剥夺诱导的凋亡，并激活细胞外信号调节激酶（ERK）和磷脂酰肌醇3激酶（PI 3激酶）信号通路。通过使用药理学试剂以及对ERK或PI 3激酶信号通路的显性干扰或组成型激活成分进行瞬时转染，我们证明ERK信号通路在BDNF对喜树碱的神经保护作用中起主要作用。此外，在喜树碱诱导的凋亡过程中，ERK在皮质神经元中被激活，抑制ERK会增加细胞凋亡。相比之下，PI 3激酶信号通路是正常培养条件下血清依赖性存活以及BDNF对血清剥夺保护作用的主要存活机制。这些结果表明，ERK信号通路是应激激活的几种神经保护机制之一，可抵消中枢神经系统神经元中的死亡信号。此外，ERK和PI 3激酶信号通路对神经元存活的相对贡献可能取决于细胞损伤的类型。
