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Northwestern team identifies first enzyme in mammalian circadian clock

A research team led by Joseph S. Takahashi, professor of neurobiology and physiology at Northwestern University, has discovered the first enzyme to play a role in the circadian clock of mammals. The team's findings are detailed in the April 21 issue of Science.

This discovery contributes another known piece to the circadian clock puzzle and should help increase researchers' understanding of circadian rhythm-related problems in humans, including jet lag, sleep disorders and affective disorders, such as depression and bipolar disease. Also, the enzyme could make an ideal target for the development of drugs to treat such problems.

"Our research provides the first evidence that a gene called casein kinase I epsilon is a critical component of the mammalian circadian clock," said Takahashi, who also is a Howard Hughes Medical Institute investigator. "This is the most exciting development to come out of my laboratory since we cloned the mammalian circadian gene, Clock, in 1997."

While casein kinase I epsilon, or CKIe, is the ninth gene to be identified with circadian rhythms in mammals, it is the first gene that acts as an enzyme.

Circadian (Latin for "about a day") clocks are known to rely on a simple and elegant feedback loop of gene activation and inhibition. When that loop is working right, normal circadian rhythms of sleep and wakefulness adhere to a 24-hour cycle. When something is awry, the sleep-wake cycle is thrown off its normal pattern.

In mammals, the clock's feedback loop begins when a pair of proteins in the cell's nucleus, activation proteins called CLOCK-BMAL1, bind to and turn on a genetic switch. This switch regulates genes that produce various negative feedback proteins, including PERIOD proteins. The proteins bind to each other and build up in the cell's cytoplasm until they reach a peak level, at which time they return to the nucleus and "shut off" the switch by inhibiting the CLOCK-BMAL1 proteins. Producti
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Contact: Megan Fellman
fellman@northwestern.edu
847-491-3115
Northwestern University
19-Apr-2000


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