"This is an 'old' gene for which we have characterized an important new role," Jirtle said.

When working properly, the M6P/IGF2r receptor protein has at least three distinct regulatory -- or "traffic cop" -- roles within a cell, said Jirtle. It is involved in activating a very potent growth inhibitor, called transforming growth factor beta. It disables a positive growth factor, insulin-like growth factor II. The receptor also works inside the cell as a shuttle craft, moving proteolytic enzymes to the lysosomes, a part of the cellular digestive system that breaks down proteins into simpler compounds.

Because the receptor is involved both in switching on a growth inhibitor and inactivating a growth factor, the researchers hypothesized that losing it might well predispose a cell to cancerous growth. Their past studies showing that the protein was abundantly present in normal liver cells, but nearly absent in cancer cells, strengthened their suspicion.

In research published earlier this year in the journal Oncogene, Jirtle's team found that liver tumors from 64 percent of patients studied had lost one copy of the gene. The deletion of one copy, or allele, means that a mutation in the remaining copy can limit or destroy a cell's ability to produce functional protein.

Next, the researchers began the arduous process of screening the large gene for one or more mutations that might disable it. Using a method to detect mismatches in genetic material, they compared strands of DNA from tumor cells and surrounding normal tissue, and discovered mutations in the tumor samples. The discovery of identical mutations in more than one tumor indicated potential "hot spots" -- regions of the gene that may be more susceptible to mutation.

"One mutation results in an altered protein that lacks the ability to insert itself into the cell membrane," according to Zeneca's De Souza, who has spent three ye
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Contact: David Rice
rice0014@mc.duke.edu
Duke University
29-Apr-1996