p38 mitogen-activated protein kinase-independent induction of gadd45 expression in nerve growth factor-induced apoptosis in medulloblastomas
p38 mitogen-activated protein kinase-independent induction of gadd45 expression in nerve growth factor-induced apoptosis in medulloblastomas
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DOI：
10.1074/jbc.m102832200
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发表时间：
2001-11-02
影响因子：
4.8
通讯作者：
Lee, VMY
中科院分区：
文献类型：
--
作者：
Chou, TT;Trojanowski, JQ;Lee, VMY
我们描述了一种新的神经生长因子(NGF)信号通路，该信号通路不依赖于JNK和p38MAPK而诱导GADD45。我们使用代表588个基因的cDNA阵列来研究差异基因表达在NGF介导的多效性反应中的作用。我们比较了接受NGF诱导凋亡的MED283-TrkA细胞和接受NGF诱导分化的PC12细胞的基因表达谱。NGF在MED283-TrkA细胞中的一个早期和特异的转录靶点是DNA损伤诱导基因GADD45。其诱导大小与突变TrkA受体转染的MED283克隆的凋亡大小直接相关。虽然GADD45参与了应激反应信号转导，但体外的激酶分析表明，NGF既不能激活c-jun氨基末端激酶(JNK)，也不能激活p38丝裂原激活的蛋白激酶(MAPK)。此外，p38 MAPK抑制剂SB203580(20um)不能阻止NGF诱导的细胞凋亡和NGF诱导的GADD45表达。这些结果表明，可能通过BRCA1对GADD45表达的差异调节可能是NGF调节多效性反应的一个潜在机制。
We describe a novel nerve growth factor (NGF)signaling pathway leading to gadd45 induction that is independent of JNK and p38 MAPK. We used cDNA arrays representing 588 genes to investigate the role of differential gene expression in NGF-mediated pleiotropic responses. We compared the gene expression profiles obtained from MED283-TrkA cells undergoing NGF-induced apoptosis to PC12 cells undergoing NGF-induced differentiation. An early and specific transcriptional target of NGF in MED283-TrkA cells was the DNA-damage-inducible gene gadd45. Its magnitude of induction directly correlated with the magnitude of apoptosis in MED283 clones transfected with mutant TrkA receptors. Although gadd45 has been implicated in stress response signaling, in vitro kinase assays indicated that NGF neither activated c-Jun NH(2)-terminal kinase (JNK) nor p38 mitogen-activated protein kinase (MAPK). Furthermore, the p38 MAPK inhibitor SB203580 (20 muM) failed to prevent NGF-induced apoptosis and NGF-induced gadd45 expression. These results suggest that differential regulation of gadd45 expression possibly through BRCA1 may be a potential mechanism whereby NGF regulates pleiotropic responses.