Single Genetic Locus Linked To Top Cancer-Targeted Biochemical Pathways

The findings, likely to have major implications for the development of anti-cancer therapies, appear in today's issue of Cell.

Pivotal in one of the pathways is the newly identified tumor suppressor ARF. The St. Jude researchers found that ARF interacts with one of the most frequently mutated tumor suppressor genes in human cancer, p53. 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 interdepartmental St. Jude research team led by Charles J. Sherr, M.D., Ph.D., an investigator of the Howard Hughes Medical Institute, had earlier found ARF 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 Sherr.

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.

Although the exact mechanism by which ARF exerts its antiproliferative effects on cells is unknown, ARF may operate, like p53, through another cell growth inhibitor called p21Cip1 , which is found at increased levels in the presence of ARF.

St. Jude Children's Research Hospital, in Memphis, Tenn, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital's work is primarily supported through funds raised by the American Lebanese Syrian Associated Charities (ALSAC). All St. Jude patients are treated regardless of their ability to pay. ALSAC covers all costs of treatment beyond those reimbursed by third party insurers, and total costs for families who have no insurance.