Study shows how nutrient levels affect enzyme associated with aging process
(Medical Xpress) -- Restricting calorie intake extends life span in many species, and a new study at the School of Medicine helps illuminate how: Low-nutrient conditions activate an enzyme that helps cells complete their normal division process.
The researchers discovered that an enzyme called AMPK, found in human cells, plays a role in choreographing the early steps of cell division. The enzyme’s response in restricted-nutrient conditions could be important during normal cell development and in stem or cancer cells, according to the study, which was published online Dec. 1 in Molecular Cell.
Cells and organisms must be capable of thriving in a tempest of fluctuating energy levels. AMPK senses when nutrients are scarce, and initiates processes that stabilize the cell’s replication cycle, a function of the enzyme that hadn’t been known before.
“We had shown in worms that AMPK is important for the link between dietary restriction and longevity,” said Anne Brunet, PhD, associate professor of genetics and senior author of the study. “This prompted us to investigate its role in mammals.”
Studying human cells, the scientists circled in on the enzyme’s role in mitosis, the process cells use to divide their genetic material into two cells. Using a chemical screening method in living cells, the scientists identified 32 proteins directly modified by AMPK, 28 of which were previously unknown. Several of these are involved in cell division.
“It’s the first time the screening method has been applied to the AMPK enzyme in living, human cells,” Brunet said.
AMPK has a pocket that binds a phosphate-donating molecule. The enzyme transfers phosphate molecules from those donors to other proteins, which regulates their functioning. It’s possible to label the phosphate-donor with molecular tags that identify it, but the labeled molecule is too bulky to fit in the normal enzyme’s pocket.
The researchers created a modified version of AMPK with a pocket big enough to bind the labeled phosphate donor — so they could track what proteins the enzyme modifies — using a technique developed by co-author Kevan Shokat, PhD, at UC-San Francisco. AMPK acts on a network of proteins responsible for completing cell division, the researchers found.
“In the face of nutrient deprivation, it’s important for the cell to complete mitosis in order to reach a safe checkpoint and prevent genomic instability,” said Brunet, adding that the finding could have implications for all dividing cells.
By identifying new molecules affected by AMPK, the findings increase the number of potential targets for treatments of conditions like cancer, Brunet said. In addition, the powerful screening system used in the study could be used for studying other enzymes, she said.
The first author of the study is former graduate student Max Banko, PhD. Graduate student Bethany Schaffer and research assistant Jamie White are co-authors on the study, which also involved researchers at UCSF, Harvard Medical School, MIT, the Howard Hughes Medical Institute, the Beth Israel Deaconess Medical Center and the University of Dundee.
The study was funded by the National Institutes of Health and by Stanford and NIH graduate fellowships.
