The NK4a-ARF locus encodes two unrelated tumor suppressors, p!6INK4i' and p!9ARF, that control cell proliferation by affecting the functions of the retinoblastoma protein and p53, respectively. The frequency of disruption of this locus by mutations and deletions in human cancer cells is second only to loss of p53. The ARF protein induces cell cycle arrest in both the Gl and G2 phases of the cell cycle in a p53-dependent manner. Mice lacking p19ARF but expressing functional p16INK4a are highly cancer prone and develop tumors early in life. Primary mouse embryo fibroblasts (MEFs) lacking ARF but expressing p 16INK4a do not undergo replicative crisis in culture and can be transformed by oncogenic Ha-Ras alone. However, proliferation of ARF-null MEFs is halted in a p53-dependent manner in response to y- or UV-irradiation, indicating that p53-mediated checkpoint control in response to DNA damage does not depend on p!9ARF function. Increased p19ARF expression extends the half-life of wild-type p53 in MEFs from 15 to -75 minutes and induces the p53-responsive gene products, p21Cipl and mdm2. In turn, the mouse ARF protein can form binary complexes with either p53 (on or off DNA) or with mdm2, as well as ternary complexes with both. We will present data showing that ARF controls a p53-dependent checkpoint that responds directly to oncogenic signals. The ARF-p53 pathway thereby provides a failsafe mechanism that counters uncontrolled proliferation by inducing either growth arrest or apoptosis.
|Number of pages||1|
|State||Published - Dec 1 1998|