The basis for cell toxicity in this instance is not

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The basis for cell toxicity in this instance is not entirely clear, but it is thought that the abnormally high amounts of p53 arrest the cell cycle and promote apoptosis. A466 Chapter 20: Cancer Table 20–3 A Punnett square showing all possible genotypes resulting from random assortment of p53 Mdm2 gametes ( Answer 20–55 ). FEMALE GAMETES p53 + Mdm2 + p53 + Mdm2 p53 Mdm2 + p53 Mdm2 p53 + Mdm2 + p53 + Mdm2 + p53 + Mdm2 + p53 + Mdm2 + p53 + Mdm2 + p53 + Mdm2 + p53 + Mdm2 p53 Mdm2 + p53 Mdm2 p53 + Mdm2 p53 + Mdm2 p53 + Mdm2 p53 + Mdm2 p53 + Mdm2 p53 + Mdm2 + p53 + Mdm2 p53 Mdm2 + p53 Mdm2 p53 Mdm2 + p53 Mdm2 + p53 Mdm2 + p53 Mdm2 + p53 Mdm2 + p53 + Mdm2 + p53 + Mdm2 p53 Mdm2 + p53 Mdm2 p53 Mdm2 p53 Mdm2 p53 Mdm2 p53 Mdm2 p53 Mdm2 p53 + Mdm2 + p53 + Mdm2 p53 Mdm2 + p53 Mdm2 MALE
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References: de Oca Luna RM, Wagner DS & Lozano G (1995) Rescue of early embryonic lethality in mdm2 -deficient mice by deletion of p53 . Nature 378, 203–206. Jones SN, Roe AE, Donehower LA & Bradley A (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378, 206–208. DATA HANDLING 20–56 A. An Arf -knockout mouse would be expected to be more prone to cancer than a wild-type mouse. In the absence of Arf, Mdm2 would be more active than in a wild-type mouse. Overactive Mdm2 would, in turn, tend to repress p53 activity more than normal. Thus, the consequence of an Arf knockout would be reduced p53 activity. If this lowered activity impaired the ability of p53 to force abnormal cells to undergo cell cycle arrest or apoptosis, more precan- cerous cells would escape detection and more tumors would form. B. A p53 +/+ Mdm2 –/– mouse will not be rescued by knockout of the Arf gene. In the absence of Mdm2, the activity of p53 will be maximized. Because Mdm2 is absent, the link between Arf and p53 is missing. Thus, no change in Arf levels can affect p53 activity, and p53 +/+ Mdm2 –/– Arf –/– mice will die just like p53 +/+ Mdm2 –/– mice do. C. Mice that express the Myc oncogene will overstimulate Arf activity, which will decrease Mdm2 activity, which will cause an increase in p53 activity. Increased p53 activity (so long as it is not increased to the point where it is toxic—see Problem 20–55) will tend to increase the mouse’s ability to force abnormal cells into cell cycle arrest and apoptosis. This increased activity of p53 operates in opposition to the proliferation-promoting activity of the Myc oncogene. In an Arf +/– mouse there is less Arf, hence, less of a decrease in Mdm2 activity and less of an increase in p53 activity. Because the prolifera- tion-promoting activity of the Myc oncogene is opposed to a lesser extent (by the lower p53 activity), Arf +/– mice generate tumors more quickly and die at a younger age. References: Quelle DE, Zindy F, Ashmun RA & Sherr CJ (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993–1000.
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