STANFORD, Calif. Researchers at the Stanford University School of Medicine have untangled two distinct ways in which a common, naturally occurring "tumor-suppressor" protein works. The separation of these two functions which can have quite different consequences could enhance efforts to develop treatment approaches that mitigate the sometimes-devastating side effects of radiotherapy and chemotherapy.
The protein, p53, is mutated or missing in more than half of all human cancers, and most cancers involve at least some compromise in its function.
Cancer is caused by two categories of mutations: those that activate oncogenes, whose protein products drive cells into overzealous replication, and those that disable tumor-suppressor genes, which code for proteins that sense this abnormal behavior and put the brakes on it.
"We knew that p53 responds to two different types of signals: DNA damage and oncogene activity," said Laura Attardi, PhD, associate professor of radiation oncology and of genetics. "We wanted to know if p53 responds to both in the same way." Attardi is senior author of a study to be published May 13 in Cell that throws light on crucial molecular details about how p53 works.
It is widely understood that p53 can temporarily or permanently shut down cell division in response to either acute damage to a cell's DNA or biochemical signals within a cell that suggest it's prone to becoming a cancer cell. In extreme cases, p53 convincingly counsels the cell to commit suicide, thereby preventing the possibility of a tumor arising.
Attardi and her colleagues created bioengineered mice in which various parts of p53 were incapacitated. This allowed them to determine which genes are activated by different parts of the protein, and to show that p53's aggressive DNA-damage response and its gentler tumor-suppression response are separable functions.
"We've determined, for the first time, that the gene exp
|Contact: Ruthann Richter|
Stanford University Medical Center