Gong Xing, Kole Labanyamoy, Iskander Karim, Jaiswal Anil K
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 2007 Jun 1;67(11):5380-8. doi: 10.1158/0008-5472.CAN-07-0323.
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.
肿瘤抑制因子p53在多种癌症中要么缺失要么发生突变。MDM2与p53相互作用会导致p53的泛素化和26S蛋白酶体降解。慢性DNA损伤会导致MDM2失活、p53稳定以及凋亡性细胞死亡。在此，我们提出一种新的不依赖MDM2/泛素化的p53稳定和瞬时激活机制。目前的研究表明，20S蛋白酶体会降解p53。在泛素高效和缺乏的细胞中均观察到p53的20S降解，这表明这种降解途径不需要p53的泛素化。胞质醌氧化还原酶[NRH：醌氧化还原酶2（NQO2）和NAD（P）H：醌氧化还原酶1（NQO1）]与p53相互作用，并保护p53免受20S蛋白酶体降解。进一步研究表明，急性暴露于辐射或化学物质会导致NQO1和NQO2的诱导，从而稳定并瞬时激活p53及其下游基因。这些结果表明，应激诱导的NQO1和NQO2会瞬时稳定p53，从而保护细胞免受应激源的不利影响。
