ARF Tumor-Suppressor Gene: A Natural Defense Against Cancer

Scientists at Cold Spring Harbor Laboratory and St.Jude Children’s Research Hospital in Memphis, Tennessee, provide new information about one of the key “gatekeepers” of cellular health: the p19ARF (ARF) tumor-suppressor gene in an article published in a recent issue of Genes and Development, Scott Lowe,PhD, of Cold Spring Harbor and his colleagues report that ARF plays a critical role in the TP53 (alias p53) tumor-suppressor pathway. “The prevailing view is that p53 is the ‘guardian of the genome,’ ” Lowe says. It can block cell proliferation after damage to the DNA through cell-cycle arrest. This gene can also stimulate the natural phenomenon of apoptosis (which halts uncontrolled cellular proliferation), following activation of the ElA oncogene.

The new findings indicate that ARF plays a role in the series of molecular events triggered by oncogenic activation of TP53 but does not play a role in the TP53 pathway that is stimulated by DNA damage. When TP53 is disabled, ARF appears to have no function, suggesting that TP53 is its only target.

Inactivation of rb Increases ARF

In 1989, Ed Harlow (then at Cold Spring Harbor), identified the relationship between the viral oncogene ElA and the retinoblastoma oncogene (rb). Harlow and collaborators found that ElA promotes cell proliferation by binding to the rb protein and thereby inactivating it. Because rb was known to down-regulate proliferation, Harlow’s finding was the first clear evidence of the relationship between an oncogene (ElA) and a tumor-suppressor gene (rb).

The new report by Lowe and his colleagues extends these findings by showing that: (1) inactivation of rb increases ARF expression, (2) ARF activates TP53, and (3) TP53 induces cell death. Hence, if ARF is mutated, the consequences are similar to a TP53 mutation. Both mutations are frequently present in cancer and leave no fail-safe mechanisms to rid the body of potentially cancerous cells.

ARF Sensitive to Apoptotic Signals

In their recent studies, Lowe, in collaboration with Charles J. Sherr,PhD, of St. Jude Children’s Research Hospital, used mouse embryo fibroblasts infected with retroviruses that carry the ElA gene. Sherr had reported in 1997 that mice devoid of a functioning copy of the ARF gene developed assorted spontaneous tumors, including fibrosarcomas and lymphomas.

The recent collaboration by Lowe and Sherr showed that cells missing ARF are insensitive to apoptotic signals. Lowe’s group found that they were able to restore apoptotic sensitivity to cells that lacked ARF by reintroducing a functioning copy of the TP19 gene.

The new studies also provide a model for increasing the sensitivity of cancer cells to chemotherapy or radiation therapy. “Many cancer drugs damage DNA, and much evidence suggests this damage kills cancer cells by activating p53-induced cell death,” Lowe explains. “ARF also activates p53, and laboratory experiments on mouse cells show that the combination of ARF and lower doses of DNA-damaging agents (radiation or chemotherapy) are very effective in inducing apoptotic cell death.” Lowe believes that if researchers can find multiple ways to trigger cell death, they may be better able to control tumor growth.