Calpain-mediated cleavage of Fbxw7 during excitotoxicity.

Neuronal cell death induced by ischemic injury has been attributed to glutamate receptor-mediated excitotoxicity, which is known to be accompanied by Ca2+ overload in the cytoplasm with concomitant activation of calcium-dependent mechanisms. More specifically, the overactivation of calpains, calcium-dependent cysteine proteases, have been associated with neuronal cell death following glutamate treatment. Previously, we observed decreased expression levels of F-box/WD repeat domain-containing protein 7 (Fbxw7) after the hyperactivation of cyclin-dependent kinase 5 (Cdk5) in cortical neurons challenged with glutamate. As determined using in vitro calpain cleavage assays, we demonstrated that the cleavage of Fbxw7 was mediated by activated calpain and attenuated in the presence of the calpain inhibitor, calpeptin. Using the rat middle cerebral artery occlusion model, we confirmed that Fbxw7 was indeed cleaved by activated calpain in the ipsilateral cortex. Based on our data, we hypothesize that the negative regulation of Fbxw7 by calpain may contribute to neuronal cell death and that the preservation of Fbxw7 by the inhibition of calpain, Cdk5, or both composes a novel protective mechanism following excitotoxicity.

Ko YU ，Song HY ，Kim WK ，Yune TY ，Yun N ，Oh YJ ... -  《-》

Site-specific phosphorylation of Fbxw7 by Cdk5/p25 and its resulting decreased stability are linked to glutamate-induced excitotoxicity.

Ko YU ，Kim C ，Lee J ，Kim D ，Kim Y ，Yun N ，Oh YJ ... -  《-》

Effect of glutamate on lysosomal membrane permeabilization in primary cultured cortical neurons.

Yan M ，Zhu W ，Zheng X ，Li Y ，Tang L ，Lu B ，Chen W ，Qiu P ，Leng T ，Lin S ，Yan G ，Yin W ... -  《-》

Activation of cyclin-dependent kinase 5 by calpains contributes to human immunodeficiency virus-induced neurotoxicity.

Wang Y ，White MG ，Akay C ，Chodroff RA ，Robinson J ，Lindl KA ，Dichter MA ，Qian Y ，Mao Z ，Kolson DL ，Jordan-Sciutto KL ... -  《-》

Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29.

Patzke H ，Tsai LH 《JOURNAL OF BIOLOGICAL CHEMISTRY》