Cyclin I-Cdk5 governs survival in post-mitotic cells.

Cdk5 has long been recognized to play an important role in development, maturation and apoptosis of postmitotic and terminally differentiated cells. Activation of Cdk5 is tightly regulated by specific activators. Cyclin I was recently characterized as the first cyclin protein that binds to and activates Cdk5. Cyclin I-Cdk5 activates the MEK-ERK pathway and results in increased Bcl-2 and Bcl-X(L) mRNA and protein levels. Lack of Cyclin I renders podocytes more susceptible to apoptosis. Interestingly, activation of Cdk5 by p35 is also involved in the podocytes' response to injury. In the absence of p35, podocytes are more prone to undergo apoptosis. Here, we propose a new model where Cdk5 plays a central role in the cellular response machinery against injury-induced apoptosis of post-mitotic cells. While Cyclin I-Cdk5 regulates Bcl-2 family proteins through activation of the MEK-ERK pathway, p35-Cdk5 directly phosphorylates and stabilizes Bcl-2.