基础分子生物学Cha.pptVIP

* * Loss of p53 is the crucial step in immortalization.  When cells enter senescence as the result of telomere shortening, p53 is activated, leading to growth arrest or apoptosis. Figure 30.41 shows that the trigger that activates p53 is the loss of the telomere-binding protein TRF2 from the chromosome ends. In effect, TRF2 protects the end of the DNA, but when it is lost, the free 3′ overhanging end activates p53 (1998; 3669). The loss of p53 is the crucial event that allows the cells to survive and divide. A variety of events can be associated with immortalization, but they converge upon causing either the loss or inactivation of p53 protein. Remember that p53 was discovered as the protein of host cells that binds the T antigen (the transforming protein) of polyomaviruses. A major part of the activity of T antigen is its ability to inactivate p53. The T antigens of different viruses work in different ways, but the consequences of the interaction are especially clear in the case of HPV E6 (the equivalent of T antigen), which targets p53 for degradation. In effect, HPV converts a target cell into a p53 – state. p53 provides an important function in immortalization, but may not be sufficient by itself. Established cell lines have usually lost p53 function, which suggests that the role of p53 is connected with the acquisition of ability to support prolonged growth. However, loss of the known functions of p53 is not enough by itself to explain immortalization, since, for example, a p53 – mouse is viable, and therefore is able to undergo the usual pattern of cell cycle arrest and differentiation. Primary cells from a p53 – mouse can pass into the established state more readily than cells that have p53 function, which suggests that loss of p53 activity facilitates or is required for immortalization (877). An interesting convergence is seen in the properties of the tumor antigens from different DNA tumor viruses, . The antigens always bind to both the cellular t