Muragaki Y, Chou T T, Kaplan D R, Trojanowski J Q, Lee V M
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA.
J Neurosci. 1997 Jan 15;17(2):530-42. doi: 10.1523/JNEUROSCI.17-02-00530.1997.
Neurotrophins act through their cognate receptors to promote the differentiation and/or survival of neuronal progenitor cells, immature neurons, and other cells. Here, we examined the effects of nerve growth factor (NGF) and its cognate receptor (Trk or TrkA) on the survival of a common childhood brain tumor, i.e., medulloblastoma, a tumor that resembles CNS neuroepithelial progenitor cells. To do this, we engineered two human medulloblastoma cell lines (i.e., D283MED and DAOY cells) to express human TrkA using a retroviral expression vector. Surprisingly, NGF-treated medulloblastoma cells expressing the TrkA receptor (D283trk and DAOYtrk cells) grown in the presence or absence of serum underwent massive apoptosis, but similar treatment did not induce apoptosis in wild-type uninfected cells, cells expressing an empty vector, or cells expressing the TrkC receptor. Furthermore, D283MED cells engineered to express the human p75 NGF receptor (D283p75) also did not undergo apoptosis. Significantly, NGF-induced apoptosis in D283trk and DAOYtrk cells can be inhibited by anti-NGF antibodies and by K-252a, an inhibitor of TrkA tyrosine phosphorylation and mimicked by high concentrations of NT3. Because NGF treatment primarily eliminated D283trk cells from the S phase of the cell cycle, this form of NGF-mediated apoptosis is cell cycle-dependent. These findings suggest that a NGF/TrkA signal transduction pathway could activate apoptotic cell death programs in CNS neuroepithelial progenitor cells and in childhood brain tumors.
神经营养因子通过其同源受体发挥作用，以促进神经元祖细胞、未成熟神经元和其他细胞的分化和/或存活。在此，我们研究了神经生长因子（NGF）及其同源受体（Trk或TrkA）对一种常见儿童脑肿瘤——髓母细胞瘤存活的影响，髓母细胞瘤是一种类似于中枢神经系统神经上皮祖细胞的肿瘤。为此，我们使用逆转录病毒表达载体构建了两个人髓母细胞瘤细胞系（即D283MED和DAOY细胞）以表达人TrkA。令人惊讶的是，在有或无血清存在的情况下生长的表达TrkA受体的经NGF处理的髓母细胞瘤细胞（D283trk和DAOYtrk细胞）发生了大量凋亡，但类似处理未在野生型未感染细胞、表达空载体的细胞或表达TrkC受体的细胞中诱导凋亡。此外，构建用于表达人p75 NGF受体的D283MED细胞（D283p75）也未发生凋亡。重要的是，抗NGF抗体和TrkA酪氨酸磷酸化抑制剂K-252a可抑制D283trk和DAOYtrk细胞中NGF诱导的凋亡，而高浓度的NT3可模拟这种凋亡。由于NGF处理主要将D283trk细胞从细胞周期的S期清除，这种形式的NGF介导的凋亡是细胞周期依赖性的。这些发现表明，NGF/TrkA信号转导途径可能激活中枢神经系统神经上皮祖细胞和儿童脑肿瘤中的凋亡细胞死亡程序。
