Overactive Cdk2 in the progression and treatment of cancer

Cyclin dependent kinase 2 (Cdk2) is commonly overactive in human cancers. This has previously been shown to cause a deregulation of the cell cycle through Rb phosphorylation and subsequent tumorigenesis. Here, we discuss a number of other effects that overactive Cdk2, particularly when in complex with Cyclin D1, has on cells and how this may possibly lead to tumor progression. Phosphorylation of Rb leads to increased expression of the spindle assembly checkpoint protein, Mad2, and therefore strengthens it. Conversely, this hyperphosphorylation prevents cell cycle arrest due to the tetraploidy checkpoint, rendering cells susceptible to polyploidy and subsequent aneuploidy. Cooperating with this mechanism of chromosomal instability, Cyclin D1/Cdk2 complexes are shown to phosphorylate Nucleophosmin and Cdh1, two proteins that play integral roles in the centrosome replication pathway. Cells expressing a Cyclin D1/Cdk2 fusion protein, D1K2, also exhibit failed cytokinesis, decreased ability to bundle supernumerary centrosomes, and phosphorylation of the multifunctional protein, PSF. Likely through a number of these mechanisms, overactive Cdk2 also promotes an epithelial to mesenchymal transition, which is characterized by a change in mitogenic signaling pathways and an increased sensitivity to small molecule inhibitors of the newly activated pathways. Together, these results show that Cyclin D1 overexpression and overactive Cdk2 likely play a number of roles in the initiation, development, and progression of human cancers. The data presented here raise questions regarding our current understanding and treatment of tumors with overactive Cdk2, and offer insight into possible new directions in the fight against this disease.