Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

Aberration in proliferation and consequently in cell cycle control is a common aspect in carcinogenesis. As master cell cycle regulating proteins in all eukaryotic cells the Cyclindependent kinases (Cdk) were identified by Leland Hartwell, Paul Nurse, and Timothy Hunt in the 1970s and 1980s. Chronological activation of respective Cdk according to respective cell cycle phase G1, S, G2 or M is mediated through association with a regulatory Cyclin subunit, phosphorylation of Cdk and binding of endogenous activators and inhibitors, as well as subcellular localization (Shapiro, 2006). In human cells four Cdk are essential components of the cell cycle machinery with key functions also in human cancer cells: Cdk1, Cdk2, Cdk4, and Cdk6 (Fig. 1) (Malumbres & Barbacid, 2009). First, Cyclin D-dependent kinases Cdk4 and Cdk6 are activated in human cell cycle in response to mitogenic signals to initiate G1 phase progression and prepare DNA duplication in S phase (Malumbres & Barbacid, 2005). Cdk4-Cyclin D or Cdk6-Cyclin D and later also Cdk2-Cyclin E complexes sequentially phosphorylate retinoblastoma proteins (Rb) on different serine and threonine residues. Resulting Rb protein inactivation is required for the transcriptional activation of genes in G1/S phase (Harbour & Dean, 2000). In G1 phase endogenous inhibitors of monomeric Cdk4 and Cdk6 like INK4 and inhibitors of Cdk2/Cdk4/Cdk6-Cyclin complexes like Cip and Kip proteins exert important influence on Cdk catalytic activity (Blain, 2008; Sherr & Roberts, 1999). Once the cell irreversibly passed restriction point R at the end of G1 phase, Cdk2-Cyclin A complex is formed, facilitating orderly execution of S phase events like DNA replication and centrosome cycle through phosphorylation of various proteins (Malumbres & Barbacid, 2005). Activation of Cdk1 by Cyclin A is required for DNA damage checkpoint control, later Cdk1-Cyclin B for G2/ M phase transition and initiation of mitosis, especially chromosome condensation and microtubule dynamics (Malumbres & Barbacid, 2009). Therefore, active Cdk1-Cyclin complexes mediate phosphorylation of about 70 substrates, e. g., minichromosome maintenance (MCM), p53, lamins, and dyneins. Initiation of cell re-entrance from G0 to G1 phase and early inactivation of Rb is assigned to Cdk3-Cyclin C (Ren & Rollins, 2004). Another Cyclin-dependent kinase, Cdk5, is involved in the regulation of neuronal function (Cruz & Tsai, 2004).