Mdm2 Regulates p53 Independently of p19^ARF in Homeostatic Tissues

Abstract

Tumor suppressor proteins must be exquisitely regulated since they can induce cell death while preventing cancer. For example, the p19^ARF tumor suppressor (p14^ARF in humans) appears to stimulate the apoptotic function of the p53 tumor suppressor to prevent lymphomagenesis and carcinogenesis induced by oncogene overexpression. Here we present a genetic approach to defining the role of p19^ARF in regulating the apoptotic function of p53 in highly proliferating, homeostatic tissues. In contrast to our expectation, p19^ARF did not activate the apoptotic function of p53 in lymphocytes or epithelial cells. These results demonstrate that the mechanisms that control p53 function during homeostasis differ from those that are critical for tumor suppression. Moreover, the Mdm2/p53/p19^ARF pathway appears to exist only under very restricted conditions.

We are grateful to Martine Roussel, Charles J. Sherr, Stephen N. Jones, Paul Lambert, and Amy Liem for providing mice and to the UWCCC Flow Cytometry Facility for help with flow cytometry. We thank Douglas Powell of the National Cancer Institute for statistical analysis of the radiosensitivity data.

This work was supported by NIH grants CA07175 (to the McArdle Laboratory for Cancer Research), CA14520 (to the University of Wisconsin Flow Cytometry Facility), and CA70718 (to M.E.P.). S.M.M. was supported by NIH predoctoral training grant CA09135.