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Molecular and Cellular Biology, January 2002, p. 370-377, Vol. 22, No. 1
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.1.370-377.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

p19ARF Is Dispensable for Oncogenic Stress-Induced p53-Mediated Apoptosis and Tumor Suppression In Vivo

Dawn Tolbert, Xiangdong Lu, Chaoying Yin, Mathew Tantama, and Terry Van Dyke*

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Received 27 July 2001/ Returned for modification 27 August 2001/ Accepted 3 October 2001

Recent studies have shown the p19ARF tumor suppressor to be involved in the response to oncogenic stress by regulating the activity of p53. This response is mediated by antagonizing the function of Mdm2, a negative regulator of p53, indicating a pathway for tumor suppression that involves numerous genes altered in human tumors. We previously described a transgenic mouse brain tumor model in which oncogenic stress, provided by cell-specific inactivation of the pRb pathway, triggers a p53-dependent apoptotic response. This response suppresses the growth of developing tumors and thus represents a bona fide in vivo tumor suppressor activity. We further showed that E2F1, a transcription factor known to induce p19ARF expression, was required for the response. Here, we use a genetic approach to test whether p19ARF functions to transduce the signal from E2F1 to p53 in this tumor suppression pathway. Contrary to the currently accepted hypothesis, we show that a deficiency in p19ARF has no impact on p53-mediated apoptosis or tumor suppression in this system. All measures of p53 function, including the level of apoptosis induced by pRb inactivation, the expression of p21 (a p53-responsive gene), and the rate of tumor growth, were comparable in mice with and without a functional p19ARF gene. Thus, although p19ARF is required in some cell types to transmit an oncogenic response signal to p53, it is dispensable for this function in an in vivo epithelial system. These results underscore the complexity of p53 tumor suppression and further indicate the existence of distinct cell-specific pathways that respond to similar stimuli.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, CB# 7295, Chapel Hill, NC 27599-7295. Phone: (919) 962-2145. Fax: (919) 966-3015. E-mail: tvdlab{at}med.unc.edu.

Molecular and Cellular Biology, January 2002, p. 370-377, Vol. 22, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.1.370-377.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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