DOI: 10.1073/pnas.2436329100. p53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1

p53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1

10.1073/pnas.2436329100

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Proteasomal degradation of p53 is mediated by two alternative pathways that are either dependent or independent of both Mdm2 and ubiquitin. The ubiquitin-independent pathway is regulated by NAD(P)H: quinone oxidoreductase 1 (NQO1) that stabilizes p53. The NQO1 inhibitor dicoumarol induces ubiquitin-independent p53 degradation. We now show that, like dicoumarol, several other coumarin and flavone inhibitors of NQO1 activity, which compete with NAD(P)H for binding to NQO1, induced ubiquitin-independent p53 degradation and inhibited wild-type p53-mediated apoptosis. Although wild-type p53 and several p53 mutants were sensitive to dicoumarol-induced degradation, the most frequent “hot-spot” p53 mutants in human cancer, R175H, R248H, and R273H, were resistant to dicoumarol-induced degradation, but remained sensitive to Mdm2-ubiquitin-mediated degradation. The two alternative pathways for p53 degradation thus have different p53 structural requirements. Further mutational analysis showed that arginines at positions 175 and 248 were essential for dicoumarol-induced p53 degradation. NQO1 bound to wild-type p53 and dicoumarol, which induced a conformational change in NQO1, inhibited this binding. Compared with wild-type p53, the hot-spot p53 mutants showed increased binding to NQO1, which can explain their resistance to dicoumarol-induced degradation. NQO1 thus has an important role in stabilizing hot-spot p53 mutant proteins in human cancer.

Bibliography

Asher, G., Lotem, J., Tsvetkov, P., Reiss, V., Sachs, L., & Shaul, Y. (2003). p53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1. Proceedings of the National Academy of Sciences, 100(25), 15065â15070.

Authors 6

Gad Asher (first)
Joseph Lotem (additional)
Peter Tsvetkov (additional)
Veronica Reiss (additional)
Leo Sachs (additional)
Yosef Shaul (additional)

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Dates

Type	When
Created	21 years, 8 months ago (Dec. 9, 2003, 1:17 p.m.)
Deposited	1 year, 7 months ago (Jan. 11, 2024, 11:45 a.m.)
Indexed	3 months ago (May 19, 2025, 10:05 a.m.)
Issued	21 years, 9 months ago (Nov. 21, 2003)
Published	21 years, 9 months ago (Nov. 21, 2003)
Published Online	21 years, 9 months ago (Nov. 21, 2003)
Published Print	21 years, 8 months ago (Dec. 9, 2003)

Funders 0

None

BibTeX

@article{Asher_2003, title={p53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.2436329100}, DOI={10.1073/pnas.2436329100}, number={25}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Asher, Gad and Lotem, Joseph and Tsvetkov, Peter and Reiss, Veronica and Sachs, Leo and Shaul, Yosef}, year={2003}, month=nov, pages={15065–15070} }

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