Sci. Aging Knowl. Environ., 18 August 2004
Molecular partner urges worm protein to trigger survival pathway
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/33/nf76
Like the little devil who wheedles the conscience of a cartoon character contemplating a fateful decision, a worm protein guides another protein in shaping the animal's future, new work reveals. The molecule--called DIN-1--coaxes another protein to stretch longevity when a particular hormone is absent. The study might help clarify how pathways that kick in during hard times also delay aging.
Mutations in the nematode insulin-related signaling pathway spur longevity by tapping into an adversity-resistance mechanism. When overheated, overcrowded, or starved, maturing worms endure by assuming an alternate guise--the semidormant, rugged dauer state--until conditions improve. Certain mutations in daf-2, the worm's version of the insulin-like receptor protein, force nematodes to enter the dauer state, in part by allowing another gene, daf-12, to promote survival. Some of the same errors in daf-2 also prolong life span. Previous studies have suggested that a liaison between the DAF-12 protein and an as-yet-unidentified hormone serves as a survival switch in young nematodes. When times are good, worms make the hormone, and DAF-12 prompts them to mature; when conditions take a downturn, hormone manufacture shuts down, and unattached DAF-12 sets survival machinery in motion. Mammalian proteins similar to DAF-12 have partners that influence their activity, so Ludewig and colleagues looked for worm molecules that guide DAF-12's workings.
To lure proteins that adhere to DAF-12, the researchers attached the molecule to a molecular fishhook and cast it into yeast cells engineered to produce random worm proteins. They reeled in DAF-12 and examined what stuck. One catch, a protein they dubbed DIN-1, resembles mammalian proteins that help govern whether hormone-recognizing molecules turn genes on or off. To investigate how DIN-1 influences DAF-12's workings, the team crippled the gene in worms. Worms enter the dauer state regardless of conditions when they carry certain alterations in DAF-12 and DAF-9, the enzyme that makes DAF-12's hormone (see "Hard Times Teach Life-Extending Lessons"). But when din-1 also malfunctioned, worms with these mutations avoided the hibernation state. The results suggest that DIN-1 normally keeps DAF-12 from sparking worm maturation and instead prompts DAF-12 to steer worms toward the dauer state.
Snafus in daf-9 that activate the dauer pathway also promote long life, so the team investigated din-1's influence on worm mortality. Defects in din-1 as well as hiccups in daf-12 cancel the longevity benefit usually provided by daf-9 mutations, suggesting that the normal versions of DIN-1 and DAF-12 promote long life when DAF-9 misfires. The researchers propose that when DAF-9 doesn't generate hormone, DIN-1 directs DAF-12 to promote dauer entry and long life.
"It's beautiful work," says molecular geneticist Cynthia Kenyon of the University of California, San Francisco. "[DAF-12] is so complicated, it needs this kind of careful analysis to ever be understood." The results show a "clear, consistent picture that [DIN-1] is a coregulator of DAF-12." However, she notes that these proteins alter life span only a small amount and at low temperatures, suggesting that "there's more to the life-span story." Further studies should reveal additional details about how genes such as din-1 guide life-altering judgments.
August 18, 2004
Suggested by Greg Liszt.
Science of Aging Knowledge Environment. ISSN 1539-6150