Calling ADAM-12

Gene probed by Missouri researchers shows promise for variety of hard-core offenders

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COLUMBIA, Mo.—Research at the University of Missouri's College of Veterinary Medicine involving several specialties points to the ADAM-12 gene, which encodes a member of the A disintegrin and metalloprotease protein family, as an important element in the battles against several difficult and persistent conditions in humans.

In a similar fashion, ADAM-12, the 40-year-old television crime series, paired a rookie with a veteran on the streets of Los Angeles. In 2011, this new rookie may show promise in arresting the development of several veteran diseases.

Scientists know the ADAM-12 protein is normally found in very low levels in adults, but during the progression of cancer, arthritis, cardiac hypertrophy and perhaps other conditions, ADAM-12 level goes up. The ADAM-12 gene encodes this membrane-anchored protein.

Alpana Ray, research associate professor in the College of Veterinary Medicine, and a team of researchers including Bimal Ray, professor of veterinary pathobiology, have been tracking down the ADAM family of genes for several years.

"ADAM-12 protein," says Alpana Ray, "which can perform multiple functions, is linked with several diseases. These include cancer, arthritis and cardiac hypertrophy. In addition, ADAM-12 is shown to mediate the neurotoxic effect of amyloid-beta protein that forms amyloid plaques in the brain of patients suffering from Alzheimer's disease. Furthermore, ADAM-12 is seen to be high in chronic wounds, and topical inhibitors of this protein may prove useful for the treatment of chronic wounds."

The team has also found evidence of ADAM-12 in the placenta, where it is found in high levels during pregnancy and is related to a dangerous condition experienced by some women late in pregnancy.

"ADAM-12 is linked with preeclampsia, which is a leading cause of pregnancy-related maternal and fetal morbidity and mortality," Alpana Ray says.

In addition, the team has chased down the protein in animal studies: "Overexpression of ADAM-12 is shown to induce obesity and weight gain in mice, while mice lacking ADAM-12 showed resistance to weight gain in response to a high-fat diet," Alpana Ray says.

At the molecular level, the team found a Z-DNA-binding silencer element that keeps the level of ADAM-12 low in normal conditions. The researchers believe if they could alter Z-DNA-binding silencer, new therapies could be right around the corner.

Alpana Ray says the findings are exciting because of the multiple activities ADAM-12 can perform.

"Some of the biological functions of this protein," she says, "which makes it so important, are proteolysis or ability to break down any protein, ability to release active growth factors that will promote cell growth and ability to attach with other cells."

In cancer, high levels of ADAM-12 could be instrumental in the breakdown of tumor membrane and release cancer cells from the original site. ADAM-12 then can help these cancer cells to attach to a different location/organ, and next, by releasing growth factors, it can fuel further growth of cancer cells and form a new tumor at distant locations.   

"We are finding that in the placenta, where ADAM-12 is highly expressed, the repressor protein (Z-DNA-binding protein) is inactive. In other tissues, where ADAM-12 expression is low, the repressor is active," Alpana Ray says. "What we don't know is how it actually works. We know co-factors are at work here. If we can identify the class of proteins that interact with Z-DNA repressor, it could lead to many therapeutic applications."

What the researchers do know is that the level of ADAM-12 protein is tightly regulated and kept very low in all adult tissues likely because of its multi-function capability: it may truly play a "good cop, bad cop" role within the body.

"However," Alpana Ray adds, "under diseased conditions, synthesis of ADAM-12 protein rises markedly, and it is believed that higher level of ADAM-12 protein is instrumental for the development of relevant diseases. It was practically unknown how and what factors regulated the synthesis of ADAM-12. We identified a novel mechanism which unravels how ADAM-12 protein level is kept under control and low in normal adult tissues."

She adds that the team has gathered the evidence to prove beyond a reasonable doubt that dysregulation of this event may be responsible for the increase of ADAM-12 protein level under many diseased conditions. Now, she says, the researchers are investigating whether this mechanism is dysfunctional in cancer cells and tissues.

Specifically, Bimal Ray notes, the next phase of the investigation will be to pursue likely suspects to determine how the Z-DNA-binding protein works.

"Most of the success in cancer therapy lies in a combination of approaches and chemotherapies, and this could become another piece of the puzzle that leads to the cure," Bimal Ray says.

Additional work will hopefully reconstruct the multiple infractions committed by high levels of ADAM-12.

"We speculate that there are multiple routes for ADAM-12 synthesis and understanding each of them will be necessary to control increase of ADAM-12 protein level under diseased conditions. In addition to cancer, arthritis, cardiac hypertrophy, chronic wound healing, Alzheimer's disease and pregnancy-related problems could be solved by understanding more on the pathways regulating expression of this protein," Bimal Ray says.

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