The Role of Cdk5 as a Cell Cycle Suppressor in Post-mitotic Neurons

Neurons of the central nervous system (CNS) leave the mitotic cycle when they leave the ventricular zone during embryonic and early postnatal development. Normally, they will never re-enter the cell cycle for the rest of the life of the organism. This rule is now known to be broken in many types of neurodegenerative disease. In these situations, nerve cells at risk for death have greatly elevated expression of cell cycle-related proteins; they have also been found to replicate their DNA. The existence of this pathway to neuronal death through the cell cycle raises the question of how a normal adult neuron suppresses cell division and places high therapeutic value on encouraging the activity of those proteins involved in the process. We have developed several lines of evidence that cyclin-dependent kinase 5 (Cdk5) is one such protein. To function as a cell cycle suppressor, Cdk5 must be located in the nucleus and it must be able to bind its cyclin-like activator, p35. Curiously, however, it does not need to retain kinase activity. Instead, its activity derives from its ability to sequester the E2F1 transcription factor and block its access to the DP1 co-factor, which greatly reduces binding to various cell cycle protein gene promoters thus inhibiting the cycle. Cdk5 stands as an excellent example of proteins whose functions are needed for the regulation of both differentiation and cell division. From this description of dual-specificity proteins, a concept is presented that the processes of division and differentiation are not so much independent as overlapping analog functions that must be balanced both during development and in the adult. The loss of balance would be expected to lead to neurodegeneration in a neuron or cancer in a less highly differentiated cell type.