Mdm2 regulates p53 independently of p19(ARF) in homeostatic tissues.
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.
O'Leary
Kathleen A
KA
Department of Oncology, University of Wisconsin, Madison, Wisconsin 53706, USA.
Mendrysa
Susan M
SM
Vaccaro
Abram
A
Perry
Mary Ellen
ME
D000818:Animals; D001835:Body Weight / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004848:Epithelium / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2