| Cell death plays an important role in development, homeostasis and pathology. This biological process is tightly controlled by the coordination of different cell death signaling pathways. Originally identified as a cyclin-dependent kinase (Cdk) due to its sequence homology to Cdc2, it has been shown that Cdk5 is activated during cell death in some situations. The aim of this study is to elucidate whether there is a general correlation between Cdk5 activation and cell death, then evaluate the regulation of Cdk5 activation during cell death and the relationship between Cdk5 activation and other signaling pathways during cell death.;By using different models in which various pathological cell deaths are induced, including rat lungs suffering from pneumonia caused by Streptococcus pneumoniae type 25, mouse limbs infected with Leishmania major, preterm lamb lungs after liquid or gas ventilation, and cyclophosphamide (CP)-treated mouse embryos, we have expanded the correlation between Cdk5 activation and cell death to a broader spectrum of systems. We therefore confidently conclude that there is a general Cdk5 activation during cell death. The finding that Cdk5 is the only Cdk that is associated with cell death in CP embryos further suggests the unique role of Cdk5 during cell death compared to other Cdks, which are master regulators of cell cycle progression. Furthermore, in CP-treated mouse embryos, by comparing the regulation of Cdk5 at the level of transcription, translation and post-translation, we have demonstrated that Cdk5 is up-regulated at the posttranslational level, i.e. kinase activity, during cell death. Additionally, this study for the first time has shown that Cdk/p25 activation is mediated by calpain activation in non-neuronal cell death. Finally, we have demonstrated that p53 and apoptosome/caspase-9/caspase-3 are not required for Cdk5/p25 activation during cell death. |
