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Mdm2 Regulates p53 Independently of p19^ARF in Homeostatic Tissues

Kathleen A. O'Leary, Susan M. Mendrysa, Abram Vaccaro, and Mary Ellen Perry^*

Department of Oncology, University of Wisconsin, Madison, Wisconsin 53706, Regulation of Protein Function Laboratory, Center for Cancer Research, National Cancer Institute—Frederick, Frederick, Maryland 21702

Received 17 June 2003/ Returned for modification 21 August 2003/ Accepted 8 October 2003

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.

Present address: Fred Hutchinson Cancer Research Center, Seattle, WA 98109.

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