NRH:Quinone Oxidoreductase 2 and NAD(P)H:Quinone Oxidoreductase 1 Protect Tumor Suppressor p53 against 20S Proteasomal Degradation Leading to Stabilization and Activation of p53
Open Access
- 1 June 2007
- journal article
- retracted article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (11), 5380-5388
- https://doi.org/10.1158/0008-5472.can-07-0323
Abstract
Tumor suppressor p53 is either lost or mutated in several types of cancer. MDM2 interaction with p53 results in ubiquitination and 26S proteasomal degradation of p53. Chronic DNA damage leads to inactivation of MDM2, stabilization of p53, and apoptotic cell death. Here, we present a novel MDM2/ubiquitination-independent mechanism of stabilization and transient activation of p53. The present studies show that 20S proteasomes degrade p53. The 20S degradation of p53 was observed in ubiquitin-efficient and -deficient cells, indicating that this pathway of degradation did not require ubiquitination of p53. The cytosolic quinone oxidoreductases [NRH:quinone oxidoreductase 2 (NQO2) and NAD(P)H:quinone oxidoreductase 1 (NQO1)] interacted with p53 and protected p53 against 20S proteasomal degradation. Further studies revealed that acute exposure to radiation or chemical leads to induction of NQO1 and NQO2 that stabilizes and transiently activates p53 and downstream genes. These results suggest that stress-induced NQO1 and NQO2 transiently stabilize p53, which leads to protection against adverse effects of stressors. [Cancer Res 2007;67(11):5380–8]Keywords
This publication has 22 references indexed in Scilit:
- Balance of Yin and Yang: Ubiquitylation-Mediated Regulation of p53 and c-MycNeoplasia, 2006
- p53 and its downstream proteins as molecular targets of cancerMolecular Carcinogenesis, 2006
- Polymorphisms in the p53 pathwayOncogene, 2006
- Deficiency of NRH:Quinone Oxidoreductase 2 Increases Susceptibility to 7,12-Dimethylbenz( a )anthracene and Benzo( a )pyrene-Induced Skin CarcinogenesisCancer Research, 2004
- Nrf2 signaling in coordinated activation of antioxidant gene expressionFree Radical Biology & Medicine, 2004
- Disruption of Dihydronicotinamide Riboside:Quinone Oxidoreductase 2 (NQO2) Leads to Myeloid Hyperplasia of Bone Marrow and Decreased Sensitivity to Menadione ToxicityPublished by Elsevier BV ,2002
- In Vivo Role of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) in the Regulation of Intracellular Redox State and Accumulation of Abdominal Adipose TissueJournal of Biological Chemistry, 2001
- NRH:quinone oxidoreductase2 (NQO2)Chemico-Biological Interactions, 2000
- Neoglycoprotein Conjugated Liposomes as Macrophage Specific Drug Carrier in the Therapy of LeishmaniasisBiochemical and Biophysical Research Communications, 1994
- Separation and characterization of isoforms of DT-diaphorase from rat liver cytosolBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1992