BACKGROUND: p63 is a member of the p53 transcription factor family. p63 is 
expressed from two promoters resulting in proteins with opposite functions: the 
transcriptionally active TAp63 and the dominant-negative DeltaNp63. Similar to 
p53, the TAp63 isoforms induce cell cycle arrest and apoptosis. The DeltaNp63 
isoforms are dominant-negative variants opposing the activities of p53, TAp63 
and TAp73. To avoid unnecessary cell death accompanied by proper response to 
stress, the expression of the p53 family members must be tightly regulated. 
NAD(P)H quinone oxidoreductase (NQO1) has recently been shown to interact with 
and inhibit the degradation of p53. Due to the structural similarities between 
p53 and p63, we were interested in studying the ability of wild-type and 
polymorphic, inactive NQO1 to interact with and stabilize p63. We focused on 
TAp63gamma, as it is the most potent transcription activator and it is expected 
to have a role in tumor suppression.
PRINCIPAL FINDINGS: We show that TAp63gamma can be degraded by the 20S 
proteasomes. Wild-type but not polymorphic, inactive NQO1 physically interacts 
with TAp63gamma, stabilizes it and protects it from this degradation. 
NQO1-mediated TAp63gamma stabilization was especially prominent under stress. 
Accordingly, we found that downregulation of NQO1 inhibits TAp63gamma-dependant 
p21 upregulation and TAp63gamma-induced growth arrest stimulated by doxorubicin.
CONCLUSIONS/SIGNIFICANCE: Our report is the first to identify this new mechanism 
demonstrating a physical and functional relationship between NQO1 and the most 
potent p63 isoform, TAp63gamma. These findings appoint a direct role for NQO1 in 
the regulation of TAp63gamma expression, especially following stress and may 
therefore have clinical implications for tumor development and therapy.