Protein Tyrosine Kinases (PTKs) are a class of enzymes that transfer gamma phosphate group from ATP onto hydroxyl moiety of tyrosine containing proteins through a reversible process referred to as phosphorylation. PTKs are divided into two groups: Receptor PTKs (RPTKs), and non-receptor PTKs (NRPTKs).
Cell cycle arrest in response to DNA damage is an important part of the mechanism used in the cell cycle to maintain genomic integrity and the cell cycle checkpoints act as control mechanisms to restrain cell cycle transition after DNA damage. The G1/S cell cycle checkpoint controls the passage of cells into the DNA synthesis phase. Two cyclin-dependent protein kinases, CDK4/6-cyclin D and CDK2-cyclin E, together with the transcription complexes that includes Rb-HDAC and E2F-DP1 are critical for controlling this checkpoint (2).
The G2/M cell cycle checkpoint prevents the cell from entering mitosis during DNA damage and CDK1-cyclin B plays a critical role in this phase of the cell cycle (3). In the presence of DNA damage, activation of DNA-PK, ATM and ATR occurs which allows these protein kinases to phosphorylate p53 (4). This leads to the dissociation of p53 from MDM2, thereby activating its transcriptional activity to synthesize CDK1 inhibitory proteins. In addition, DNA damage leads to the activation of Chk1 and Chk2 which can phosphorylate and inhibit the activity of CDC25, thereby preventing the activation of CDK1. The signaling pathways feeding into the cell cycle incorporate various oncogenes and tumor suppressors and are therefore a central target for genetic alterations in human cancers (5).Defects in many of the proteins that regulate the cell cycle have been implicated in cancer formation and progression. Key among these are p53, the retinoblastoma protein (Rb) and its related proteins, p107 and Rb2/p130, and CDK inhibitors (p15, p16, p18, p19, p21, p27). The Rb (Rb/p16(INK4a)/cyclin D1) and p53 (p14(ARF)/MDM2/p53) pathways are the two main cell-cycle control pathways frequently targeted in tumorigenesis, and the alterations occurring in each pathway depend on the tumor type (6).