NQO1 stabilizes p53 through a distinct pathway.
Wild-type p53 is a tumor-suppressor gene that encodes a short-lived protein that, upon accumulation, induces growth arrest or apoptosis. Accumulation of p53 occurs mainly by posttranslational events that inhibit its proteosomal degradation. We have reported previously that inhibition of NAD(P)H: quinone oxidoreductase 1 (NQO1) activity by dicoumarol induces degradation of p53, indicating that NQO1 plays a role in p53 stabilization. We now have found that wild-type NQO1, but not the inactive polymorphic NQO1, can stabilize endogenous as well as transfected wild-type p53. NQO1-mediated p53 stabilization was especially prominent under induction of oxidative stress. NQO1 also partially inhibited p53 degradation mediated by the human papilloma virus E6 protein, but not when mediated by Mdm-2. Inhibitors of heat shock protein 90 (hsp90), radicicol and geldanamycin, induced degradation of p53 and suppressed p53-induced apoptosis in normal thymocytes and myeloid leukemic cells. Differences in the effectiveness of dicoumarol and hsp90 inhibitors to induce p53 degradation and suppress apoptosis in these cell types indicate that NQO1 and hsp90 stabilize p53 through different mechanisms. Our results indicate that NQO1 has a distinct role in the regulation of p53 stability, especially in response to oxidative stress. The present data on the genetic and pharmacologic regulation of the level of p53 have clinical implications for tumor development and therapy.
Asher
Gad
G
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Lotem
Joseph
J
Kama
Rachel
R
Sachs
Leo
L
Shaul
Yosef
Y
D000818:Animals; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009687:Nuclear Proteins; D018384:Oxidative Stress; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2; D011808:Quinone Reductases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C041831:NADH dehydrogenase (quinone); D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2