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Cancer Sentry Flashes Two-tiered Warning

Tumor Suppressor Protein Distinguishes Diseased from Dividing Cells

A protein better known as the most important natural protection against cancer has a surprisingly dynamic life in healthy cells, HMS researchers report in a new study.

The findings create a new framework for understanding the function of this famous protein, p53, in normal and diseased cells. New insights may help scientists identify new drug targets and devise optimal therapeutic strategies for the experimental cancer drugs now in preclinical development or early clinical trials.

Alexander Loewer (left) and Galit Lahav show a suprising role for the protein p53 in healthy cells. Photo by Joshua Touster.

Baseline Behavior

When it comes to protecting people against cancer, the p53 molecule stands out for its superpowers. More than 50,000 studies in the last 30 years testify to the tumor-suppressing prowess of the p53 protein, whose gene is missing or malfunctioning in most human cancers, and to the scientific interest in figuring out how to manipulate p53 to kill mutated cells more efficiently while safeguarding normal cells.

In the new study, time-lapse movies of individual healthy cells show spontaneous bursts of the p53 protein when the molecule was assumed to be off duty. Sometimes called the guardian of the genome for its response to catastrophic breaks, p53 now also appears to be on a hair-trigger alert for the transient nicks and dings suffered by the replicating genome in normal dividing cells, the researchers found.

“It’s an excitable behavior, like a jack-in-the-box, where even a small agitation makes the protein jump to its high level,” said Galit Lahav, HMS assistant professor of systems biology and senior author of the paper, published July 9 in the journal Cell.

This basal behavior of the protein has remained hidden until now, because each dividing cell fires up a p53 pulse at a different time, effectively hiding the infrequent and asynchronous bursts from scientists who measure p53 activity by averaging millions of cells together.

Real vs. Possible Danger

The work provides a new twist on p53’s abilities by showing that the protein must distinguish between common benign DNA breaks in dividing cells and potentially dangerous mutation-causing damage. 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 spontaneous events and serious damage.

Healthy cells: This time-lapse movie shows spontaneous p53 pulses as individual cells divide over 24 hours.

Damaged cells: In this time-lapse movie taken over 24 hours, damaging radiation triggers simultaneous and repeated pulses of p53 in individual cells.

Movies courtesy of Alexander Loewer

The individual p53 pulses look the same, but the consequences are different. “Remarkably, the intensity and duration of these p53 pulses were similar under both conditions,” wrote Shelley Berger of the University of Pennsylvania in a commentary in the same issue of Cell. 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.”

Single-cell Imperative

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.

“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. “This is extremely important for cancer research and treatment. Looking only at what the population is doing as a whole might mask the true behavior and lead to wrong conclusions.” Her 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. This type of study combines 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.

For more information, students may contact Galit Lahav at galit@hms.harvard.edu.

Conflict Disclosure: The authors declare no conflicts of interest.

Funding Sources: The National Institutes of Health, German Research Foundation, Charles A. King Trust, American Cancer Society, and P. and E. Taft Postdoctoral Fellowship; the authors are solely responsible for the content of this work.