Study shows p53's pathological responses to DNA damage are irrelevant to tumor suppression
By Melissa Lee Phillips | September 6, 2006
The unpleasant side effects of cancer treatments may not be necessary for successful tumor suppression, according to a paper in this week's Nature. Researchers report that widespread cell death caused by the tumor suppressor p53 in response to DNA damage is not required for p53 to block tumor formation. Instead, p53 stops tumor cells by responding specifically to oncogenic mutations.
"There's a growing understanding that p53 responds to many different types of stresses," said Laura Attardi of Stanford University in California, who was not involved in the study. "Some of those may be more central in tumorigenesis than DNA damage per se."
p53 induces apoptosis and cell-cycle arrest in cells with damaged genomes, and this response has been thought to underlie its ability to stop tumor formation, said the new study's senior author, Gerard Evan of the University of California, San Francisco (UCSF). These cellular pathologies also cause immune suppression, bone marrow depletion, hair loss, and other side effects of cancer therapies. "That has always been considered the inevitable downside of p53 acting as a tumor suppressor," Evans told The Scientist.
To see if this widespread cell death is necessary for tumor suppression, researchers led by Maria Christophorou, also of UCSF, examined DNA damage and tumor development in mice in which p53 can be reversibly turned on and off.
They first turned on p53 in mice for six days while exposing them to gamma irradiation. As expected, mice with functional p53 showed high levels of cell death in radiosensitive tissues, while mice without active p53 showed no such cell death. However, neither group of mice was protected against development of lymphoma.
"You'd think that if you have a situation where p53 is culling a large number of damaged cells, that that would make some difference (for subsequent tumor development), but it's not in this system," Attardi told The Scientist.
When the researchers turned off p53 during radiotherapy but turned it back on eight days later, the mice suffered no cell death or other cellular pathology but did show significant protection against lymphoma development - even though p53 did not kill off cells in response to DNA damage.
The results "clearly show you don't have to have p53 there when you damage the DNA to get tumor suppression," said Scott Lowe of Cold Spring Harbor Laboratory in New York, who was not involved in the study.
p53 signaling can be initiated not only by generalized DNA damage, but also by specific oncogenic mutations that disrupt the cell cycle. To see if this type of signaling could be responsible for p53's late protective effect against lymphoma development, the researchers examined the tumor suppressor p19ARF, which does not respond to DNA damage but activates p53 in response to aberrant cell proliferation. They found that p19ARF is necessary for p53 restoration to protect against radiation-induced lymphoma.
Instead of suppressing tumors by killing all damaged cells, p53 suppresses them by killing only those cells in which the damage has generated oncogenic mutations, according to Evan. P19ARF "activates p53 only in cells that really are in danger of giving you cancer," Evan said.
However, it's hard to say if "this will universally apply to every context or every tissue type," according to Attardi.
In humans, it's known that telomere shortening caused by DNA damage can induce p53 signaling, said Lowe. Laboratory mice do not suffer from telomere shortening, so the authors "couldn't assess whether that type of DNA damage could be relevant for activating p53's function as a tumor suppressor," he told The Scientist.
If p53's pathological response to DNA damage proves to be irrelevant to tumor formation in humans, blocking p53 activity during cancer therapies could alleviate unpleasant side effects, Evan suggested. "We could use drugs that will block that and yet we wouldn't suffer an increased cancer risk as a consequence as long as p53 is allowed to become active at some later point in time."
Melissa Lee Phillips
Links within this article
M.A. Christophorou et al., "The pathological response to DNA damage does not contribute to p53-mediated tumour suppression," Nature, published online September 6, 2006.
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