What makes cells stop dividing and growing

Scientists have discovered a biochemical switch that seals a cell’s fate. 

A buildup of the protein GATA4 forces cells to enter a permanently static state known as senescence, researchers report in the Sept. 25 Science. The discovery sheds light on a complex biological process linked to aging and cancer, and may help scientists better understand and treat aging-related diseases.

Senescence — in which cells stop growing and dividing — results from serious stress and genetic damage, says study coauthor Stephen Elledge, a geneticist at Harvard Medical School. GATA4 helps turn on this response in cells. The researchers found that senescent cells contained higher levels of GATA4, and producing the protein in human connective tissue cells turned the cells senescent.

GATA4 is a new link in a biological chain of events that causes senescence, says geriatrician James Kirkland of the Kogod Center on Aging at the Mayo Clinic in Rochester, Minn. There’s a clear connection between senescent cells and age-related diseases like Alzheimer’s disease and atherosclerosis, he says. The researchers found that GATA4 accumulated with age, building up to greater concentrations in the kidneys and livers of older mice and in the brain cells of older humans. Targeting GATA4 may create new therapies for age-related diseases, Kirkland says. “This opens the door to at least considering that, and doing additional experiments to test that.”

In healthy, dividing cells, GATA4 is quickly gobbled up and broken down. But this cleanup process slows down in damaged cells, causing the protein to build up and initiate senescence, the researchers found. This finding helps explain an apparent conundrum from previous studies showing that a cell’s self-digesting activity could promote or prevent a senescent fate, says experimental pharmacologist David Gewirtz of Virginia Commonwealth University in Richmond. The researchers believe that while widespread digestion of cellular materials can encourage senescence, breaking down GATA4 in particular does just the opposite.  

The protein seems to act independently of two other proteins previously known to link DNA damage with senescence, Elledge says. GATA4 exerts its control by directing the behavior of other proteins, including one that prompts senescent cells to produce a collection of inflammatory chemicals, the researchers report. These chemicals attract the attention of the immune system — typically a good thing — but can also promote senescence and tumor growth in neighboring cells. The study’s results indicate that GATA4 may be primarily responsible for controlling the production of this inflammation-inducing cocktail, says Kirkland. If this control is shown to hold only in senescent cells, he says, GATA4 could be targeted to limit inflammation.

It’s not feasible to turn off GATA4 completely, Elledge says: The protein plays a crucial role in development, especially in the heart. But he says it may be useful to target the protein specifically in senescent tissues.

Gewirtz says it remains to be seen how and if GATA4 can be used therapeutically. While the new study doesn’t completely clarify the process of senescence, it’s an important contribution to the field, he says. “It’s one more piece of the puzzle.”