Scientists have developed transgenic mice that don't get deadly liver scarring known as cirrhosis--even if they are exposed to environmental toxins or swill the equivalent of gallons of whiskey a day. The research shows a possible way to prevent cirrhosis, and also reveals that some proteins, thought to be specialists, may have more than one trick up their sleeve.
When the liver is injured by infection or toxins like alcohol, it repairs the damage by activating smooth, muscular liver cells. Chronic damage leads to a surfeit of repair cells that block blood vessels. Eventually, the liver begins to starve and die. What starts the repair process is a molecular chain reaction, set off by messenger proteins, that eventually activates a protein called C/EBPB.
Medical scientists Martina Buck and Mario Chojkier at the University of California, San Diego, wanted to know what C/EBPB does and how it gets turned on. Using radioactive tracers, they found that a phosphorous molecule has to attach in a certain spot. Further biochemical studies revealed that C/EBPB usually keeps liver repair in check by activating proteins called caspases. But when phosphorous attaches, caspases are inhibited instead. Smooth liver cells build up, and the result is cirrhosis.
To see if this discovery could help prevent liver disease, the researchers bred transgenic mice with the version of C/EBPB that couldn't bind phosphorus. Even when exposed to a dangerous toxin, the mice did not develop cirrhosis; control animals, meanwhile, quickly fell ill. The researchers, who report their work in the 26 October issue of Molecular Cell, hope to soon create an altered version of the protein that will work in humans.
The findings are "remarkable," says biochemist Steven McKnight at the University of Texas Southwestern Medical Center, Dallas, because they show that C/EBPB, previously known only to regulate the transcription of DNA, also regulates the activity of other proteins--two tasks thought to be independent and unrelated until very recently. The discovery of proteins with such different functions, he says, challenges the basic premise that proteins evolved to each tackle a single, specialized task.