A protein better known as the most important protection against cancer has a surprisingly dynamic life in healthy cells, Harvard Medical School (HMS) researchers report in a new study.
Time-lapse movies of single cells show spontaneous bursts of the p53 protein in healthy cells when the molecule was assumed to be off duty. Sometimes called the guardian of the genome for its response to catastrophic breaks, p53 now appears to be on a hair-trigger alert also for the transient nicks and dings suffered by the replicating genome in normal dividing cells, the researchers found.
“It’s an excitable behavior, like Jack-in-the-Box, where even a small agitation makes the protein jump to its high level,” says Galit Lahav (pictured), assistant professor of systems biology at HMS and senior author of the paper published.
In the scientific movies and by the researchers’ calculations, the pulses of accumulating p53 protein looks the same in a healthy dividing cell as it does when a cell is zapped by destructive gamma radiation. This basal behavior of the protein has remained hidden until now because each cell fires up a p53 pulse at a different time and only when dividing, effectively hiding the infrequent and asynchronous bursts from scientists who measure p53 activity by averaging millions of cells together.
But this is not the end of the story. The group has shown that p53 activation in healthy cells and in response to severe damage has different consequences. If there is no confirmation of sustained serious damage, then the protein allows the cell to carry on. In contrast, severe damage triggers the protein to take drastic action, such as kill a potentially rogue cell.
“There are a lot of false alarms,” said Alexander Loewer, first author and postdoctoral fellow. “The system goes off spontaneously and then switches to damage mode where it uses additional information to distinguish between a false alarm and a house that is really burning.”
“It is a combination of two main mechanisms,” Lahav said. “One is extremely sensitive; p53 will pop up with even the tiniest amount of damage. The other mechanism waits to see if the alarm is real.”
The findings highlight the complexity of a system that must maintain a delicate balance between preserving the integrity of the genome to prevent cancer and tolerating lower levels of damage intrinsic to growing or dividing cells.
Even though p53 has been studied intensively for decades, ever since its role in cancer became clear, this may be the first discovery of an ability to discriminate between serious damage and chance events. When it comes to protecting people against cancer, one molecule (and the gene that makes it) stands out for its superhero powers. More than 50,000 studies in the last 30 years testify to the crucial tumor suppression prowess of the p53 protein, whose gene is missing or malfunctioning in most human cancers.
“To develop new insights into the mechanisms and function of signaling pathways, it is important to monitor the basal dynamics of proteins in individual cells,” said Lahav, whose lab also studies how the p53 signaling network responds to various types of DNA damage in individual cells.
In fact, this study started out as a second look at a control of another experiment. “I thought it was peculiar seeing p53 pulses in the control cells,” Loewer said. “For me it was important to see how the cells behaved without damage so I could understand how they responded to damage.”
In healthy cells, Loewer and his co-authors found spontaneous p53 pulses correlated with cell-cycle events associated with intrinsic DNA damage, such as the genome replication phase of the individual dividing cells. Radiation-damage triggers a p53 pulse as well, but the sustained severe damage prompts continued pulsing and the p53 activity induces the full stress response.
This approach of measuring basal dynamics in individual cells can be applied to other important molecular pathways of health and disease, the researchers say. These types of studies combine math and biology to allow researchers to measure the dynamic properties of biological systems and how the individual components change over time, a field known as systems biology.
Illustration: Harvard Medical School.
Harvard Medical Center News (w/video) (07/20/10)
Abstract (Cell; 2010 Jul 9;142(1):89-100)