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Newly found gene linked to cancer biology.

Newly found gene linked to cancer biology

When molecular biologists announced last month they had discovered the gene causing neurofibromatosis -- the disease made famous in the movie "The Elephant Man" -- They told colleagues and reporters they had no idea how the gene caused the disfiguring neurological disease (SN: 7/28/90, p.61). They weren't lying. They simply didn't know that some of their co-workers, who had skipped the Washington, D.C. press conference, had just solved the riddle.

While television cameras focused on two of the gene's discoveries -- University of Utah's Raymond L. White and Francis S. Collins of the University of Michigan in Ann Arbor -- White's co-worker Robert Weiss remained hunched over a keyboard in Salt Lake City. He was engaged in a painstaking computer search that compared the newly discovered gene's predicted amino-acid sequence with the amino-acid sequences of thousands of known proteins. Suddenly, almost unbelievably, a match came up: The protein causing neurofibromatosis, the computer declared, is very closely related to proteins already under intense scrutiny by other researchers for their role in cancer.

That discovery, described in the Aug. 10 CELL, has elated researchers in both the neurofibromatosis (NF) and cancer fields. Typically, scientists fail to find any significant sequence similarity between a newly identified, disease-causing protein and well-known proteins, says Robert Weinberg, a molecular biologist working with cancer genes at the Massachusetts Institute of Technology in Cambridge. Without such a match, researchers might spend years just figuring out what their newly discovered gene or protein really does. "It could well have been the case that this dismal paradigm would have been true for NF as well," he says.

As it turns out, the disease-causing protein, called NF1, belongs to a family called guanosine-triphosphatase-activating proteins, or GAPs. Cancer researchers are fascinated by the GAP family because these proteins appear critical as regulators of cell division. For example, one variety of GAP normally deactivates a gene product called ras. If ras can avoid deactivation by GAP, it can trigger uncontrolled cell proliferation, including a number of human cancers.

The computer match-up suggests that NF1, like other GAPs, suppresses abnormal cell division, putting the NF gene in a class of tumor-suppressor genes known as anti-oncogenes. Patients with neurofibromatosis have a mutated version of the NF gene -- one whose product apparently cannot halt cell division triggered by ras or a ras-like protein. The resulting uncontrolled growth appears as cancer-like masses around the peripheral nerves of people bearing the mutant gene.

"Gap is one of the better-understood molecules" involved in regulating cell division, says Michael Wigler, who studies cellular signaling mechanisms at the Cold Spring Harbor Laboratory on Long Island. "A lot of drug companies have been working on ras and GAP, and it may well be that NF people will be the first to benefit from that work."

Jackson B. Gibbs, who investigates GAPs at Merck Sharp & Dohme Laboratories in West Point, Pa., agrees cautiously that the newly identified NF-GAP link "might have pharmaceutical implications." For example, he says, a drug that can modify ras-GAP interaction might prove useful for neurofibromatosis patients.

In any case, scientists say, the discovery is sure to boost collaboration among researchers working with cancer and neurofibromatosis, accelerating progress in both arenas. "We've just taken a crash course in oncology," says NF-gene co-discoverer David Viskochil of the University of Utah. He says his group is racing to identify NF1's precise function. However, he adds, "everybody else who has ras systems going has got a head start on us. We're playing catch-up now. We're scrambling."

Globally, neurofibromatosis affects one in 3,500 people, including an estimated 100,000 individuals in the United States. Although the disease is commonly associated with Joseph Merrick--the severely deformed 19th-century Londoner depicted in "The Elephant Man" -- researchers today believe Merrick actually suffered from a much rarer disorder called Proteus syndrome
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Author:Weiss, Rick
Publication:Science News
Date:Aug 18, 1990
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