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J. Biol. Chem., Vol. 278, Issue 12, 10368-10373, March 21, 2003
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From the NAD(P)H:quinone oxidoreductase 1 (NQO1)
has been proposed to stabilize p53 via a redox mechanism involving
oxidation of NAD(P)H as a consequence of the catalytic activity of
NQO1. We report that treatment of HCT-116 human colon carcinoma cells
with the NQO1 inhibitor ES936 had no effect on the levels of p53
protein. ES936 is a mechanism-based inhibitor of NQO1 that irreversibly blocks the catalytic function of the enzyme. This suggests that a redox
mechanism involving NQO1-mediated NAD(P)H oxidation is not responsible
for the stabilization of p53. We also examined the ability of the NQO1
protein to associate with p53 using co-immunoprecipitation experiments.
Results from these experiments demonstrated co-immunoprecipitation of
NQO1 with p53 and vice versa. The association between p53 and NQO1 was
not affected by treatment of HCT-116 cells with ES936, demonstrating
that the association was not dependent on the catalytic activity of
NQO1. A comparison of isogenic HCT-116 p53+/+ and HCT-116 p53
Interaction of Human NAD(P)H:Quinone Oxidoreductase 1 (NQO1)
with the Tumor Suppressor Protein p53 in Cells and Cell-free
Systems*
,,,,¶
Department of Pharmaceutical Sciences,
School of Pharmacy and Cancer Center, University of Colorado Health
Sciences Center, Denver, Colorado 80262 and the § Department
of Biochemistry, Center in Molecular Toxicology, and the
Vanderbilt-Ingram Cancer Center, Vanderbilt University School of
Medicine, Nashville, Tennessee 37232-6305
/
cells demonstrated an interaction of NQO1 and p53 only in the p53+/+
cells. Experiments performed in an in vitro transcription/translation system utilizing rabbit reticulocyte lysates confirmed the interaction of NQO1 and p53. In these experiments a full-length p53 coding region was used to express p53 in the presence
of recombinant NQO1 protein. An association of p53 and NQO1 was also
observed in primary human keratinocytes and mammary epithelial cells.
In studies where mdm-2 co-immunoprecipitated with p53, no association
of mdm-2 with NQO1 was observed. These data demonstrate an association
between p53 and NQO1 that may represent an alternate mechanism of p53
stabilization by NQO1 in a wide variety of human cell types.
*
This work was supported by Health and Human Services
RO1 Grants CA51210, ES09554, and CA70856. This work was presented in part at the 93rd annual meeting of the American Association of Cancer
Research, April 6-10th 2002, San Francisco, CA.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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