p63 splicing variants lacking NH2-terminal transactivating domain, known as Delta Np63, are thought to antagonize p53 and p63 functions and are suggested to play roles in keratinocyte differentiation. Here, we show that Delta Np63 has a dual-regulatory effect on the activity of its own promoter in NPC-076 cell. Down-regulation of the transcriptional activity is observed when Delta Np63 is present in low levels. In contrast, up-regulation of Delta Np63 transcriptional activity is observed when Delta Np63 is expressed at higher levels. The down-regulation effect is abolished when the p53-binding site of the Delta Np63 promoter is mutated. In sharp contrast, similar mutation does not affect the up-regulation of the Delta Np63 transcriptional activity under the same experimental conditions. Further study shows that the upregulation is correlated with the activation of the STAT3, as the blockade of STAT3 nuclear translocation abolishes the up-regulation by Delta Np63. Thus, Delta Np63 exerts a bidirectional regulation of the Delta Np63 transcriptional activity in NPC-076 cell. (c) 2006 Elsevier Inc. All rights reserved.