By studying a little-known yeast too primitive to get diseases, Johns Hopkins researchers have uncovered a surprising link between two processes at play in heart disease and cancer in people.
In experiments with yeast known as S. pombe, the researchers discovered that a gene that helps the organism make cholesterol also helps it survive when oxygen is scarce. The finding, described in the March 25 issue of Cell, offers a new strategy for killing infectious yeast, but it also suggests that cells' efforts to make cholesterol and detect oxygen levels might be connected in people, too.
"We were simply trying to establish that this yeast could be a model for studying cholesterol-related activities in human cells," says the study's leader, Peter Espenshade, Ph.D., assistant professor of cell biology in Johns Hopkins' Institute for Basic Biomedical Sciences. "We certainly didn't expect to find a completely new role for this gene."
It's already well established that human cells can both make cholesterol and sense oxygen. In people, high levels of cholesterol in the blood are a major risk factor for heart disease, and many human cancer cells are able to survive despite being in tumors' oxygen-starved centers.
"We don't know yet whether cholesterol production and oxygen sensing are connected in human cells, but now we're trying to find out," says Espenshade.
In people, the gene in question, known as SREBP, controls other genes whose products help make or import cholesterol. Cholesterol-lowering drugs called statins mimic this gene's natural role by triggering cells to import more cholesterol, clearing the artery-clogging stuff from the blood.
Despite the obvious medical relevance of SREBP, no one had ever looked at the equivalent system -- or even determined whether there was one -- in yeast, the simple, single-celled relatives with which we share many genes. Because yeast can be easily manipulated and studied, Espenshade figured they might be a good model for figuring out exactly how SREBP is turned on, what it does and how it's shut off -- if the organism has an equivalent process.
Turning first to databases of the entire genetic sequences of various yeast, Espenshade sought yeast genes that looked like SREBP and its binding partner SCAP. Nothing turned up in the well-studied S. cerevisiae, or brewer's yeast, but S. pombe seemed to have the right stuff.
Graduate student Adam Hughes then examined the role of these similar genes to prove that they in fact duplicate the human process. Indeed, the yeast gene they called sre1 triggered activation of cholesterol-producing genes, aided by a gene called scp1 that behaves like SCAP.
As in humans, sre1 somehow gets turned on when cholesterol levels are low, increasing the cell's production of cholesterol. As cholesterol builds up in the cell, sre1 is gradually turned off.
"Essentially, SREBP and sre1 both try to maintain an optimal level of cholesterol in the cells," says Espenshade.