Activation of CDK involves binding of CDKs with their

Activation of CDK involves binding of CDKs with their respective cyclins at the C-terminal via noncovalent interactions and leads to the accessibility of ATP to the catalytic site for phosphorylation of threonine. A list depicting the association of cyclins with CDKs and their overexpression in various cancers has been presented in Table 1. Some of the CDKs do not require cyclin for activation; for instances, such as viral cyclins (cyclins from a virus), CDK5 activators (p35 and p39 have no homology with cyclins), RINGO/Speedy family (small proteins with no homology to cyclins) [34], [35]. The endogenous ligands that activate the CDKs are mainly cyclins. These are classified as cyclin A, cyclin B, cyclin C, cyclin D, cyclin E, cyclin F, cyclin H, cyclin K, cyclin L and Cyclin T. These cyclins play a significant role in ABT 702 dihydrochloride progression by activation of ATP binding site. Cyclin A forms a complex with CDK1 and CDK2 and helps in the regulation of S phase [11], [36]. Cyclin B is also called as maturation or mitosis promoting factor as it forms complex with CDK1 and controls the M phase of the cell cycle [11], [36]. Cyclin C and H activate CDK8 which in turn plays a significant role in RNAPII transcription and also inhibits the lipogenesis [17], [37]. Cyclin D in complex with CDK4 and CDK6 controls the G1 phase of cell cycle [38]. Cyclin E helps in the Rb/E2F transcription via formation of a complex with the CDK2 and controls G1-S phase [39]. Cyclin K helps in the RNAPII transcription by forming a complex with CDK12 and CDK13 [22], [23], [40]. Cyclin L and CDK11 associate to perform RNA splicing. Cyclin T with CDK9 plays a major role in RNAPII transcription [41]. Cyclin Y/CDK14 drives the Wnt/β-catenin pathway [42]. The cyclin-dependent kinase deactivation is carried out by a particular group of proteins cyclin-dependent kinase inhibitors (CDKIs). These group of proteins blocks kinase activity by interfering with the interaction of cyclin-CDK complex [43]. The inhibition of CDK naturally occurs during a G1 phase in response to signals from damaged DNA. In the eukaryotic cells, there are two types of naturally occurring (CDKIs) families namely the INK4 (inhibitor of CDK4/6) family and the CIP/KIP (inhibit other CDKs) [44]. The INK4 family comprises of p16INK4a, p18INK4c, p15INK4b, and p19INK4 which are specific inhibitors of CDK4 and CDK6, that binds to the CDK monomers [45]. These proteins are also reported to play a major role in tumor suppression, aging, apoptosis and DNA repair [46]. CIP/KIP proteins are nonspecific and bind to cyclin and CDK or cyclin/CDK complex. This family of proteins enhances complex cyclin D-CDK4/6 formation by activation of cyclin D [43]. The dysregulated activation of CDKs has been associated with various cancers, viral infections [47], [48], Alzheimer [49], Parkinson [50], [51], renal diseases [52] and ischemia [47], [48]. The role of CDKs in the pathogenesis of various diseases has encouraged an intensive search for potent and selective pharmacological inhibitors of CDKs [53].