Neuronal Cell Cycle Regulation of Cdk5 in Alzheimer’s Disease

The cell cycle is a highly conserved mechanism that controls the cells decision to proliferate and regulate the process once it starts. Typically, the cell cycle is divided into four phases, namely G1 (first gap), S (DNA synthesis), G2 (second gap), and M (mitosis). The cell cycle process is regulated by the sequential expression, activation, and inhibition of Cyclin-dependent kinases (CDKs) associated with activating subunits, the cyclins, as well as two families of Cyclin-dependent kinase inhibitors (CKIs)–the Kip/Cip family of proteins (p21, p27 and p57) and the INK4 family (p16, p15, p19 and p18) [1-3]. There are ten Cdks and nine cyclins in mammal tissues that have been described to date. After mitogenic initiation, synthesized D-type cyclins bind to and activate Cdk4 and Cdk6. These Cdks target several proteins, chief among them the tumor suppressor protein, retinoblastoma (RB). Phosphorylated RB releases the E2F1 transcription factor which binds to DNA and allows cells to enter G1. The cyclin E/Cdk2 complex is required for transition from G1 to S phase. Later, in M phase, Cyclin B/Cdk1 activation is triggered allowing the cell to proceed through cytokinesis. During all four stages of the cell cycle, the activity of both Cdks and CKIs are tightly controlled by transcription, translation, and ubiquitin-mediated proteolysis [4-7].