Cell cycle regulation after exposure to ionizing radiation

When cells are exposed to ionizing radiation, they initiate a complex respo nse that includes the arrest of cell cycle progression in G1 and G2, apopto sis and DNA repair. DNA is an important subcellular target of ionizing radi ation, but oxydative damage to plasma membrane lipid initiates signal trans duction pathways that activate apoptosis and that may play a role in cell c ycle regulation. How is DNA damage converted into intracellular signals for cell cycle arrest! The ataxia telangectasia mutant (ATM) protein and/or th e DNA-dependent protein kinase (DNA-PK), that are bath activated by DNA dam age, may initiate cell cycle arrest by activating the p53 tumor suppressor protein. The p53 protein acts as a transcription factor and regulates expre ssion of several components implicated in pathways that regulate cell cycle progression. The best known, p21(WAF1/CIP1) protein, is an inhibitor of cy clin-dependent kinases (CDK), a family of protein kinases known as key regu lators of cell cycle progression. p21(WAF1/CIP1) was shown to be able to in hibit several CDK; but is most effective toward G1/S cyclins. Other CDK inh ibitors, p27(KIP1) and p15(INK4b) are activated by irradiation and contribu te td the GI arrest. Moreover, radiation-induced G2 arrest was shown to req uire inhibitory phospharylation of the kinase cdc2 via an ATM-dependent pat hway. Mutations in cell cycle regulatory genes are common in human cancer a nd cell cycle regulatory deficiency can lead to increase resistance to ioni zing radiation in cancer cells. The major function of p53-dependent G1 arre st may be elimination of cells containing DNA damage whereas G2 arrest foll owing radiation has been shown to be important in protecting cells from dea th. Cell cycle checkpoints offer a new set of potential targets for chemoth erapeutic compounds, especially the G2 checkpoint. Thus, abrogation of the G2 checkpoint with methylxanthines such as caffeine or protein Kinase inhib itors such as staurosporine and UCN-01 (7-hydroxystaurasporine) was found t o sensitize cells to ionizing radiation. These data did not lead to clinica l applications, but confirm targeting of the G2 checkpoint may be an import ant strategy for cancer therapy.