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Genetic Cancer LocusBy Sean Henahan, Access Excellence
 Memphis,
TN (12/8/97)- The discovery of a single genetic locus associated with
many human cancers should have major implications for the development of
future cancer therapies.
Researchers at St. Jude Children's Research Hospital have identified a new tumor suppressor gene called ARF. While in the process of investigating this gene, they made a related discovery with possibly even farther reaching implications. They have identified a single genetic locus called INK4a encodes protein products that regulate the most frequently targeted biochemical pathways in human cancers. The St. Jude researchers discovered that ARF interacts with one of the most frequently mutated tumor suppressor genes in human cancer, p53. They report that tumor suppression by ARF in mice could not occur if p53, which causes cells with defective DNA to arrest their growth and to self-destruct, is itself defective, missing, or otherwise nonfunctional. The research team had previously discovered that ARF appeared to be embedded in INK4a. "This economical, overlapping organization of both the ARF and INK4a genes in the same chromosomal location, observed in both mice and humans, is not seen anywhere else in mammals," explained Charles J. Sherr, M.D., Ph.D., an investigator of the Howard Hughes Medical Institute. The other cancer-related biochemical pathway, previously discovered, involves a protein separately encoded by INK4a that affects the activity of another tumor suppressor, the retinoblastoma protein, RB. "What is most surprising," said Sherr, "is that a single genetic locus, INK4a/ARF, encodes two different products that regulate the two biochemical pathways involving p53 and RB." Mutations and deletions that adversely affect the INK4a/ARF locus are very common in different forms of human cancer. Sherr and his team confirmed ARF as a tumor suppressor by finding that, when ARF is eliminated or knocked-out in mice, the mice develop cancers. At two months of age, mice deprived of ARF began to develop cancer spontaneously and, by six months, a third exhibited malignant tumors. Treating the mice with a known carcinogen or with X-rays hastened the onset of tumors. Conversely, mouse cell lines missing the protein encoded by ARF promptly stopped proliferating when the ARF protein was reintroduced in the cells via a retroviral vector. The exact mechanism by which ARF exerts its antiproliferative effects on cells is unknown. The researchers believe ARF may operate, like p53, through another cell growth inhibitor called p21Cip1 , which is found at increased levels in the presence of ARF. The research appears in the November 27, 1997 issue of Cell.
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