Scientists at Cold Spring Harbor Laboratory and
St.Jude Childrens 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, Harlows
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 Childrens 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. Lowes 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.