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Vol. 59, Issue 2, 263-268, February 2001
Department of Pharmaceutical Sciences, School of Pharmacy and
Cancer Center, University of Colorado Health Sciences Center,
Denver, Colorado
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.
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