IGFBP-3 is a direct target of transcriptional regulation by ΔNp63α in squamous epithelium

Delta Np63 alpha is a nuclear transcription factor that maintains epithelial progenitor cell populations, is overexpressed in several epithelial cancers, and can negatively regulate apoptosis. However, the mechanisms by which Delta Np63 alpha promotes cell survival are unclear. Delta Np63 alpha has been reported to act as a transcriptional repressor, but specific target genes directly repressed by Delta Np63 alpha remain unidentified. Here, we present evidence that Delta Np63 alpha functions to negatively regulate the proapoptotic protein IGFBP-3. Disruption of p63 expression in squamous epithelial cells increases IGFBP-3 expression, whereas ectopic expression of Delta Np63 alpha down-regulates IGFBP-3. Delta Np63 alpha binds to sites in the IGFBP-3 gene in vivo and can modulate transcription through these sites. Furthermore, Delta Np63 alpha and IGFBP-3 expression patterns are inversely correlated in normal squamous epithelium and squamous cell carcinomas. These data suggest that IGFBP-3 is a target of transcriptional repression by Delta Np63 alpha and that this repression represents a mechanism by which tumors that overexpress p63 may be protected from apoptosis.