Okamoto Shu-ichi, Li Zhen, Ju Chung, Scholzke Marion N, Mathews Emily, Cui Jiankun, Salvesen Guy S, Bossy-Wetzel Ella, Lipton Stuart A
Center for Neuroscience and Aging, Apoptosis and Cell Death Research Program, The Burnham Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3974-9. doi: 10.1073/pnas.022036399.
Myocyte enhancer factor-2 (MEF2) transcription factors are activated by p38 mitogen-activated protein kinase during neuronal and myogenic differentiation. Recent work has shown that stimulation of this pathway is antiapoptotic during development but proapoptotic in mature neurons exposed to excitotoxic or other stress. We now report that excitotoxic (N-methyl-D-aspartate) insults to mature cerebrocortical neurons activate caspase-3, -7, in turn cleaving MEF2A, C, and D isoforms. MEF2 cleavage fragments containing a truncated transactivation domain but preserved DNA-binding domain block MEF2 transcriptional activity via dominant interference. Transfection of constitutively active MEF2 (MEF2C-CA) rescues MEF2 transcriptional activity after N-methyl-D-aspartate insult and prevents neuronal apoptosis. Conversely, dominant-interfering MEF2 abrogates neuroprotection by MEF2C-CA. These results define a pathway to excitotoxic neuronal stress/apoptosis via caspase-catalyzed cleavage of MEF2. Additionally, we show that similar MEF2 cleavage fragments are generated in vivo during focal stroke damage. Hence, this pathway appears to have pathophysiological relevance in vivo.
肌细胞增强因子2（MEF2）转录因子在神经元和肌细胞分化过程中被p38丝裂原活化蛋白激酶激活。最近的研究表明，在发育过程中，该信号通路的激活具有抗凋亡作用，但在暴露于兴奋性毒性或其他应激的成熟神经元中则具有促凋亡作用。我们现在报告，对成熟大脑皮质神经元的兴奋性毒性（N-甲基-D-天冬氨酸）损伤会激活半胱天冬酶-3、-7，进而切割MEF2A、C和D亚型。含有截短的反式激活结构域但保留DNA结合结构域的MEF2切割片段通过显性干扰阻断MEF2转录活性。组成型活性MEF2（MEF2C-CA）转染可在N-甲基-D-天冬氨酸损伤后挽救MEF2转录活性并防止神经元凋亡。相反，显性干扰MEF2可消除MEF2C-CA的神经保护作用。这些结果确定了一条通过半胱天冬酶催化切割MEF2导致兴奋性毒性神经元应激/凋亡的途径。此外，我们表明在局灶性中风损伤期间体内会产生类似的MEF2切割片段。因此，该途径在体内似乎具有病理生理学相关性。
