| Cell death is an important element of development, tissue maintenance and disease. This biological process is tightly controlled by different cell death signaling pathways and a number of genes have been implicated in the regulation of cell death. Cyclin-dependent kinase 5 (Cdk5), identified due to its sequence homology to Cdc2, is a gene that is activated during cell death. The aim of this study is to investigate the roles of Cdk5 by examining the relationship of Cdk5 to different pathways involved in cell death, then evaluate the regulation of Cdk5 activation during cell death and whether Cdk5 activity is required for the induction of cell death.;By using different models in which massive cell death was induced by different toxins, including cyclophosphamide (CP)-treated mouse embryos, cyclohexamide (CHX) or camptothecine (CPT)-treated mouse embryonic fibroblast cell lines and measuring the modulation of different cell death related genes, such as caspase-3, calpain and lysosomal proteases, cathepsins, we have shown that the activation of Cdk5 is dispensible of the activity of caspase-3, calpain, and the lysosomal proteases, cathepsins. Furthermore, the finding that Cdk5 is activated without the generation of p25, an activator of Cdk5 during cell death, suggests that other activators for Cdk5 activation exist during cell death. Additionally, Inhibition of the production of Cdk5 activators, p25 and p29, by calpain inhibitor or down-regulation of Cdk5 activity by RNAi reveals Cdk5-independent cell death; and the mode of cell death is not altered in these situations. We therefore conclude that Cdk5 activation during cell death is a result of cell death rather than an initiator of cell death. |
