The Ink4a tumor suppressor gene product, p19(Arf), interacts with MDM2 and neutralizes MDM2's inhibition of p53

Jason Pomerantz, Nicole Schreiber-Agus, Nanette J. Liégeois, Adam Silverman, Leila Alland, Lynda Chin, Jason Potes, Ken Chen, Irene Orlow, Han Woong Lee, Carlos Cordon-Cardo, Ronald A. DePinho

Research output: Contribution to journalArticle

1262 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)713-723
Number of pages11
JournalCell
Volume92
Issue number6
DOIs
StatePublished - Mar 20 1998

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Pomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H. W., Cordon-Cardo, C., & DePinho, R. A. (1998). The Ink4a tumor suppressor gene product, p19(Arf), interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell, 92(6), 713-723. https://doi.org/10.1016/S0092-8674(00)81400-2