A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death.
A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death.
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细胞外信号调节激酶 5 和肌细胞增强因子 2 在髓母细胞瘤细胞死亡中的新作用。
DOI：
10.1158/0008-5472.can-04-2283
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发表时间：
2005
期刊：
影响因子：
11.2
通讯作者：
Pomeroy,ScottL
中科院分区：
文献类型：
--
作者：
Sturla,Lisa-Marie;Cowan,ChristopherW;Guenther,Lillian;Castellino,RobertC;Kim,JohnYH;Pomeroy,ScottL
神经营养素-3受体酪氨酸激酶C（TrkC）的表达与髓母细胞瘤患者的良好预后相关。这可能是由于TrkC激活诱导的肿瘤细胞凋亡增加。神经营养素-3/TrkC诱导的细胞凋亡被丝裂原活化蛋白（MAP）激酶（MAPK）药理拮抗剂SB 203580和PD 98059抑制。除了细胞外信号调节激酶（ERK）-1/2外，PD 98059还抑制最近鉴定的神经营养素应答性MAPK，ERK 5（大MAPK 1）。在本研究中，我们调查ERK 5和其靶向肌细胞增强因子2（MEF 2）的神经营养素-3/TrkC诱导的髓母细胞瘤细胞死亡的贡献。神经营养素-3不仅增强ERK 5磷酸化，而且显著增强ERK 5的特异性靶点MEF 2的转录活性。ERK 5和MEF 2的过表达诱导神经营养素3反应性和非反应性髓母细胞瘤细胞系（Daoy-trkC和Daoy）和斑片状杂合子小鼠髓母细胞瘤原代培养物的细胞死亡统计学显著增加。只有那些表达MAP/ERK激酶5（MEK 5）加ERK 5或MEF 2结构的细胞发生凋亡，表明过度表达任何一种都足以诱导髓母细胞瘤细胞死亡。显性负性MEF 2或ERK 5激活剂MEK 5的小干扰RNA的表达显著抑制神经营养素-3诱导的细胞死亡。显性阴性MEF 2构建体还阻断了MEK 5/ERK 5诱导的细胞死亡，支持了ERK 5下游MEF 2的作用。免疫共沉淀研究揭示了磷酸化ERK 5与MEF 2在神经营养素-3应答中的直接相互作用。我们对神经营养素-3/TrkC诱导的细胞凋亡机制的研究已经确定了MEK 5/ERK 5和MEF 2在细胞死亡中的新作用，这表明这些分子可以用于诱导TrkC表达和非表达髓母细胞瘤细胞的细胞凋亡。
Expression of the neurotrophin-3 receptor, tyrosine kinase C (TrkC), is associated with favorable prognosis in medulloblastoma patients. This may be due to increased tumor apoptosis induced by TrkC activation. Neurotrophin-3/TrkC–induced apoptosis is inhibited by the mitogen-activated protein (MAP) kinase (MAPK) pharmacologic antagonists SB203580 and PD98059. In addition to extracellular signal-regulated kinase (ERK)-1/2, PD98059 also inhibits the more recently identified neurotrophin-responsive MAPK, ERK5 (big MAPK 1). In the present study, we investigate the contribution of ERK5 and its target myocyte enhancer factor 2 (MEF2) to neurotrophin-3/TrkC–induced medulloblastoma cell death. Neurotrophin-3 not only enhanced ERK5 phosphorylation but also significantly enhanced the transcriptional activity of MEF2, a specific target of ERK5. Overexpression of both ERK5 and MEF2 induced a statistically significant increase in cell death of neurotrophin-3–responsive and nonresponsive medulloblastoma cell lines (Daoy-trkC and Daoy) and primary cultures ofpatchedheterozygous mouse medulloblastomas. Only those cells expressing MAP/ERK kinase 5 (MEK5) plus ERK5 or MEF2 constructs underwent apoptosis, indicating that overexpression of either is sufficient to induce medulloblastoma cell death. Expression of a dominant-negative MEF2 or small interfering RNA for the ERK5 activator, MEK5, significantly inhibited neurotrophin-3–induced cell death. The dominant-negative MEF2 construct also blocked MEK5/ERK5-induced cell death, supporting a role for MEF2 downstream of ERK5. Coimmunoprecipitation studies revealed direct interaction of phosphorylated ERK5 with MEF2 in response to neurotrophin-3. Our investigation of the mechanism of neurotrophin-3/TrkC–induced apoptosis has identified a novel role for both MEK5/ERK5 and MEF2 in cell death, suggesting that these molecules can be exploited to induce apoptosis in both TrkC-expressing and nonexpressing medulloblastoma cells.
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DOI：
10.1016/s0169-328x(96)00135-0
发表时间：
1996-12-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Lin, X;Shah, S;Bulleit, RF
通讯作者：
Bulleit, RF
影响因子：
3.8
作者：
Weldon, CB;Scandurro, AB;Burow, ME
通讯作者：
Burow, ME
影响因子：
2.7
作者：
Kim, JYH;Nelson, AL;Pomeroy, SL
通讯作者：
Pomeroy, SL
肌细胞增强因子 2 (MEF2) 与丝裂原激活蛋白激酶 ERK5/BMK1 的相互作用。
影响因子：
14.9
作者：
Chih;O. Ornatsky;J. C. McDermott;T. Cruz;C. Prody
通讯作者：
C. Prody
影响因子：
56.9
作者：
Mao, ZX;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME