Apoptosis

Edited by: Steven Benowitz A. Strasser, A.W. Harris, T. Jacks, S. Cory, "DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2," Cell, 79:329-39, 1994. (Cited in more than 110 publications through October 1996) Comments by Tyler Jacks, Howard Hughes Medical Institute, Massachusetts Institute of Technology Center for Cancer Research; and Andreas Strasser, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia CELL SLEUTHING: From left, Suzanne Cory, Andreas Strasser, and Alan Harris of the Walter and Eliza Hall Institute of Medical Research study how cells die. The p53 tumor suppressor gene, which is mutated in as many as half of all human cancers, must be functioning for apoptosis-or programmed cell death-to occur when the DNA of immune system cells is damaged by radiation during cancer treatment. If p53 is missing or mutated, apoptosis is inhibited. The oncogene bcl-2, which also is mutated in cancer, has the opposite effect of the normal p53; it halts apoptosis in such damaged cells, promoting cell survival. These responses prompted the authors of this paper to look for synergistic effects between the two genes in mice that lacked p53 and carried bcl-2. Earlier, scientists had shown that p53 was important for apoptosis in undifferentiated T cells following DNA damage by irradiation (S.W. Lowe et al., Nature, 362:847-49, 1993; A.R. Clarke et al., Nature, 362:849-52, 1993). They found that cells that were missing p53 wouldn't die despite such damage. Using mature mouse T cells that were stimulated to enter the cell cycle, Tyler Jacks and his colleagues proved that apoptosis can be induced by irradiation independent of p53. That means another unknown pathway is operating in this cell type following DNA damage, says Jacks, a Howard Hughes Medical Institute assistant investigator at the Massachusetts Institute of Technology Center for Cancer Research. In mice specially bred with lymphocytes that lacked p53 but carried bcl-2, apoptosis was blocked after DNA damage. The work showed that bcl-2 can block this p53-independent cell death, implying that bcl-2 acts "downstream of p53," notes Jacks, who collaborated with lead author and senior research fellow Andreas Strasser and his team at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. SUPRISED: MIT's Tyler Jacks was sure that p53 was needed for apoptosis. The finding is important, maintains Jacks, because "it's the first time this has been shown with respect to DNA damage." Many chemotherapeutic agents damage cells' DNA, and many work largely by inducing apoptosis, Jacks explains. "If you understand the p53-independent pathway, perhaps you could develop mechanisms or strategies to kill p53 mutant tumor cells." No one knows the mechanism at work in apoptosis that occurs without p53, he says. Nor do scientists understand why only certain cell types undergo apoptosis in response to DNA damage. "That means that p53 is required for only a subset of apoptotic mechanisms." "We have a sense for the importance of this [p53] mechanism in chemotherapeutics," Jacks maintains. He notes that cancer cells lacking p53 "will undergo apoptosis in response to chemotherapeutic agents, which already tells you that there is a p53-independent way for these cells to die." If this is a rare occurrence, then it suggests that p53 is important in this kind of DNA damage response, he adds. "If one could understand the p53 response to this type of DNA damage and manipulate it, in theory it could lead to improved chemotherapeutic agents." Strasser points out that scientists haven't absolutely proved that irradiation and the resulting DNA damage are what kills cancer cells. "It's an important finding that these treatments used in the clinic can actually kill cells in the absence of p53, at least in lymphoid cells." Jacks was surprised by the finding. He assumed that the response to radiation-damaged DNA would have invariably involved p53. "That's one of the reasons I think the paper has gotten so much attention," he speculates.

Apoptosis

The Scientist Staff

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