Scientists Learn How Cells Limit Th...( alResearch. Sustained exposure to str...)

The cell's need for relief accounts for an earlier finding: that the cell produces high levels of chaperones only briefly, even if stressful conditions persist. This self-limiting response suggested a feedback loop in which chaperones cause the shutdown of their own production.

Morimoto and his coworkers focused on a master protein called heat shock factor, which is known to spur the genes that encode chaperones to make more of them during stress. Earlier this year they reported test tube experiments showing that certain chaperone proteins can bind to and regulate heat shock factor, thus providing a molecular feedback loop to precisely control the level of chaperones made following stress.

Now they have found in the cell's nucleus another signal molecule they call HSBP-1, the first known "off-switch" regulator of chaperone production. HSBP-1 binds both to the chaperones and to heat shock factor and prevents the factor from activating genes to produce more chaperones.

"This is the first time we've seen a new regulatory molecule other than chaperones that controls the heat shock response," Morimoto said. The new molecule, he said, may explain the decline in cellular health that occurs with age.

"As cells age, the heat shock response doesn't function properly -- just when it needs to be most efficient. This molecule may be the reason why. It works together with the chaperones to sense what's going on and shuts off the response."

The heat shock response was first observed in fruit flies and later in yeast. Morimoto's group was first to clone a human heat shock gene in 1985, and since then the heat shock response has been regarded by scientists as universal. HSBP-1 exists in higher multicellular organisms.

"Many of our cells, especially nerve cells, divide rarely, if at all," Morimoto said. "The reason
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Contact: Bill Burton
b-burton@nwu.edu
847-491-3115
Northwestern University
1-Jul-1998