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Research ArticleArticle

Rapid Polyubiquitination and Proteasomal Degradation of a Mutant Form of NAD(P)H:Quinone Oxidoreductase 1

David Siegel, Adil Anwar, Shannon L. Winski, Jadwiga K. Kepa, Kathryn L. Zolman and David Ross
Molecular Pharmacology February 2001, 59 (2) 263-268; DOI: https://doi.org/10.1124/mol.59.2.263
David Siegel
Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado
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Adil Anwar
Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado
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Shannon L. Winski
Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado
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Jadwiga K. Kepa
Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado
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Kathryn L. Zolman
Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado
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David Ross
Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado
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Abstract

The NAD(P)H:quinone oxidoreductase 1 (NQO1)*2 polymorphism is characterized by a single proline-to-serine amino acid substitution. Cell lines and tissues from organisms genotyped as homozygous for the NQO1*2 polymorphism are deficient in NQO1 activity. In studies with cells homozygous for the wild-type allele and cells homozygous for the mutant NQO1*2 allele, no difference in the half-life of NQO1 mRNA transcripts was observed. Similarly, in vitro transcription/translation studies showed that both wild-type and mutant NQO1 coding regions were transcribed and translated into full-length protein with equal efficiency. Protein turnover studies in NQO1 wild-type and mutant cell lines demonstrated that the half-life of wild-type NQO1 was greater than 18 h, whereas the half-life of mutant NQO1 was 1.2 h. Incubation of NQO1 mutant cell lines with proteasome inhibitors increased the amount of immunoreactive NQO1 protein, suggesting that mutant protein may be degraded via the proteasome pathway. Additional studies were performed using purified recombinant NQO1 wild-type and mutant proteins incubated in a rabbit reticulocyte lysate system. In these studies, no degradation of wild-type NQO1 protein was observed; however, mutant NQO1 protein was completely degraded in 2 h. Degradation of mutant NQO1 was inhibited by proteasome inhibitors and was ATP-dependent. Mutant NQO1 incubated in rabbit reticulocyte lysate with MG132 resulted in the accumulation of proteins with increased molecular masses that were immunoreactive for both NQO1 and ubiquitin. These data suggest that wild-type NQO1 persists in cells whereas mutant NQO1 is rapidly degraded via ubiquitination and proteasome degradation.

Footnotes

    • Received August 31, 2000.
    • Accepted October 26, 2000.
  • Send reprint requests to: Dr. David Siegel, School of Pharmacy C238, UCHSC, 4200 East Ninth Ave., Denver CO 80262. E-mail:david.siegel{at}uchsc.edu

  • This work was supported by National Institutes of Health Grants CA51210 and ES09554 and Environmental Protection Agency Grant R825281010. S.L.W. is supported by National Research Science Award CA79446.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (2)
Molecular Pharmacology
Vol. 59, Issue 2
1 Feb 2001
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Research ArticleArticle

Rapid Polyubiquitination and Proteasomal Degradation of a Mutant Form of NAD(P)H:Quinone Oxidoreductase 1

David Siegel, Adil Anwar, Shannon L. Winski, Jadwiga K. Kepa, Kathryn L. Zolman and David Ross
Molecular Pharmacology February 1, 2001, 59 (2) 263-268; DOI: https://doi.org/10.1124/mol.59.2.263

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Research ArticleArticle

Rapid Polyubiquitination and Proteasomal Degradation of a Mutant Form of NAD(P)H:Quinone Oxidoreductase 1

David Siegel, Adil Anwar, Shannon L. Winski, Jadwiga K. Kepa, Kathryn L. Zolman and David Ross
Molecular Pharmacology February 1, 2001, 59 (2) 263-268; DOI: https://doi.org/10.1124/mol.59.2.263
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