p53-independent apoptosis is induced by the p19ARF tumor suppressor.
p19(ARF) is a potent tumor suppressor. By inactivating Mdm2, p19(ARF) upregulates p53 activities to induce cell cycle arrest and sensitize cells to apoptosis in the presence of collateral signals. It has also been demonstrated that cell cycle arrest is induced by overexpressed p19(ARF) in p53-deficient mouse embryonic fibroblasts, only in the absence of the Mdm2 gene. Here, we show that apoptosis can be induced without additional apoptosis signals by expression of p19(ARF) using an adenovirus-mediated expression system in p53-intact cell lines as well as p53-deficient cell lines. Also, in primary mouse embryonic fibroblasts (MEFs) lacking p53/ARF, p53-independent apoptosis is induced irrespective of Mdm2 status by expression of p19(ARF). In agreement, p19(ARF)-mediated apoptosis in U2OS cells, but not in Saos2 cells, was attenuated by coexpression of Mdm2. We thus conclude that there is a p53-independent pathway for p19(ARF)-induced apoptosis that is insensitive to inhibition by Mdm2.
Tsuji
Keitaro
K
Department of Pharmacology, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Mizumoto
Kiyohisa
K
Sudo
Haruka
H
Kouyama
Keisuke
K
Ogata
Etsuro
E
Matsuoka
Masaaki
M
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D002453:Cell Cycle; D016923:Cell Death; D002460:Cell Line; D002469:Cell Separation; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007763:Lac Operon; D009687:Nuclear Proteins; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
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; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2