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In the lessons about G1-phase regulation we will also cover the topic Gamma-Irradiation. This type of irradiation at higher dose is usually harmful for cells since it causes extensive protein and DNA damage. Cells, however, have a certain mechanism to protect themselves. They usually undergo cell cycle arrest in G1- and G2-phase and try to repair the damaged DNA. If they continued growing without repair, mutations would be stably introduced causing these cells to become cancer cells or cancer cells become more aggressive. At this point we have to introduce another important tumor suppressor protein, the p53 protein, which is basically inactivated in all cancers. P53 in the true sense is both tumor suppressor and oncogene, since a point mutation in one p53 gene, which leads to an altered protein will inactivate wild-type p53 proteins as well, since p53 proteins can dimerize with themselves. If one of proteins is mutant the resulting phenotype is also mutant. P53 is also called the ´Guardian Angel of the Genome´ and has a number of different functions. P53 is a transcription factor under conditions which cause stress to the cell such as DNA damage. We will hear about other important functions in one of the next lessons. As shown in the figure, when cells are irradiated the p53 level increases and a CKI (Cyclin-Dependent Kinase Inhibitor) called p21cip1 is made in amounts inactivating the G1-phase CDKs CDK4/6 and CDK2 causing cell cycle arrest. If the DNA damage is too severe and cannot be repaired, cells commit suicide which is called Apoptosis. Again the initial protein responsible in this case is the p53 protein. Now you understand why cancer cells like to inactivate p53, because one of the hallmarks of cancer is to escape from Programmed Cell Death, which is a protective mechanism to kill possible cancer cells. For cells to undergo apoptosis the pRb protein is degraded. Since the pRb protein is often mutated or missing, cells which are wild-type p53 and lack pRb undergo by all means apoptosis and usually in cancer cells this combination does not exist or only in genetically manipulated cells in the laboratory. In the next figure the consequences of mutant or missing p53 protein are shown. In this case there is no induction of the synthesis of p21 and no cell cycle arrest in G1-phase thus causing DNA-damaged cells to enter S-phase for DNA replication. The consequences are devastating since this will introduce mutations in important genes and can cause chemoresistant and more aggressive tumors among those cells which survive this treatment.
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