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NQO1 stabilizes p53 through a distinct pathway
Gad Asher1, Joseph Lotem, Rachel Kama
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
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.
Insights
NAD(P)H: quinone oxidoreductase 1 (NQO1) stabilizes the tumor suppressor p53, particularly during oxidative stress. This finding has implications for cancer therapy by revealing new ways to regulate p53 levels.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- Wild-type p53 is a crucial tumor suppressor protein.
- p53 stability is regulated by posttranslational modifications, primarily proteasomal degradation.
- NAD(P)H: quinone oxidoreductase 1 (NQO1) has been implicated in p53 stabilization.
Purpose of the Study:
- To investigate the role of wild-type NQO1 in p53 stabilization.
- To determine if NQO1's effect on p53 is dependent on oxidative stress.
- To compare the mechanisms of p53 stabilization by NQO1 and heat shock protein 90 (hsp90).
Main Methods:
- Utilized wild-type and polymorphic NQO1 in experiments with endogenous and transfected p53.
- Induction of oxidative stress to observe NQO1-mediated p53 stabilization.
- Compared the effects of NQO1 inhibition (dicoumarol) and hsp90 inhibition (radicicol, geldanamycin) on p53 degradation and apoptosis.
Main Results:
- Wild-type NQO1, unlike inactive polymorphic NQO1, stabilizes p53.
- NQO1-mediated p53 stabilization is enhanced under oxidative stress.
- NQO1 partially inhibits HPV E6-mediated p53 degradation but not Mdm-2-mediated degradation.
- Hsp90 inhibitors induce p53 degradation and suppress apoptosis, with different effectiveness compared to dicoumarol.
Conclusions:
- NQO1 plays a distinct role in regulating p53 stability, especially under oxidative stress.
- NQO1 and hsp90 stabilize p53 through different mechanisms.
- Understanding the regulation of p53 levels by NQO1 has potential clinical implications for cancer therapy.