The INK4a gene encodes two distinct growth inhibitors - the cyclin- dependent kinase inhibitor p16(Ink4a), which is a component of the Rb pathway, and the tumor suppressor p19(Arf), which has been functionally linked to p53. Here we show that p19(Arf) potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19(Arf) and MDM2 physically interact and that p19(Arf) blocks MDM2-induced p53 degradation and transactivational silencing, suggests that p19(Arf) functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent tumor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathways, Rb and p53.
Bibliographical noteFunding Information:
The authors thank C. Sherr for the anti-p19 Arf antisera, S. Efrat for the SV40 large T antigen expression construct, A. Levine for the MDM2 and dominant-negative mutant (KH215) p53 expression constructs, D. Beach for the cDNAs encoding mouse p16 Ink4a and p19 Arf , N. Bouck for the CAT reporter constructs, R. Tjian for the pC53SN3 wild-type p53 expression construct, S. Deb for the MDM2 deletion mutants, Jerry Shay for H1299 cells, M. Kastan and C. Finlay for helpful discussions, and Michael Cammer for confocal microscopy assistance. J. P. is a Howard Hughes Medical Institute Medical Student Research Training Fellow. N. S.-A. is a Special Fellow of the Leukemia Society of America (Grant 3712–98). N. J. L. is supported by the Medical Scientist Training Program grant. H.-W. L. is supported by the National Institutes of Health training grant. L. A. is a recipient of the James S. McDonnell Foundation Scholar award and an NIH Mentored Clinician Scientist award. C. C.-C. is supported by grants CA47538, CA47179, and CADK97650 from the National Institutes of Health. R. A. D. is supported by grants (R01HD28317, R01EY09300, and R01EY11267) from the National Institutes of Health, as well as the Irma T. Hirschl Award. The Albert Einstein Cancer Center Core grant P30CA13330 support is acknowledged.
All Science Journal Classification (ASJC) codes
- General Biochemistry,Genetics and Molecular Biology