The transcriptional activation of p53 results in an of its target gene p21, which encodes a inhibitor protein that binds to and inhibits HC-030031 cyclin complexes in G1. The first faltering step of the DNA damage response is the recruitment of indicator things to the websites of DNA damage where in fact the ATM/ATR kinases are activated. These kinases can phosphorylate and activate either the transcription factor p53 straight or they activate the Chk2 kinase, which often can phosphorylate and activate p53. Because CDK activity is necessary for progression in to S phase, activation of this checkpoint effects in a cycle arrest in late G1 and therefore, this checkpoint is called G1 checkpoint. Furthermore, a second DNA damage checkpoint exists, which acts in G2: the ATM and ATR kinases can also phosphorylate and activate the Chk1 kinase, which phosphorylates and inactivates the dual specificity phosphatase Cdc25C resulting in its cytoplasmic sequestration. Cdc25C could be the phosphatase responsible for removing two inhibitory phosphates from CDK1, that will be required for activation of CDK1 and subsequent entry into mitosis. Hence, DNA damage induced inhibition of Cdc25C is mediated by Chk1 and prevents the entry in to mitosis constituting the G2 DNA damage checkpoint. Treatment of those tumor cells with DNA damaging agents results in a cell cycle arrest solely in G2, because most human tumor cells have lost the big event Endosymbiotic theory of the G1 checkpoint. This scenario allows the selective targeting of cancer cells by abrogating the residual G2 charge by the utilization of pharmacological inhibitors of the G2 checkpoint, therefore driving cells into mitosis in the existence of DNA damage ultimately causing the induction of a mitotic catastrophe associated with cell death. The Chk1 kinase is important for the G2 arrest upon chemotherapy induced DNA damage and can be effortlessly inhibited by the indolocarbazole compound UCN 01 that serves being an ATP competitive inhibitor. Sequential treatment of p53 deficient tumefaction cells with DNA damaging medications and UCN 01 results in an purchase CAL-101 successful abrogation of the G2 arrest and entry in to mitosis. Similar to the treatment with anti mitotic medications, cells activate the spindle checkpoint once they enter mitosis with damaged chromosomes, probably as a result of failure of a suitable chromosome congression. Eventually, mitotically arrested cells activate apoptotic pathways that involve the release of pro apoptotic proteins from mitochondria and the following activation of caspases. Hence, mitotic disaster upon G2 checkpoint abrogation shows a type of apoptosis triggered in mitosis. Significantly, as seen for the induction of apoptosis after treatment with anti microtubule drugs, mitotic apoptosis can also be determined by a practical spindle checkpoint.