Regulation of VDR by ΔNp63α is associated with inhibition of cell invasion

• DOI: 10.1242/jcs.049619
• Publication Date: 2009-07-22T01:49:56Z
• Authors: Ramakrishna Komma...; Mary K. Leonard; Stefanie Lewis; Rose-Anne Romano; Satrajit Sinha; Madhavi P. Kadakia
• Keywords: Transcriptional Activation; 0303 health sciences; Tumor Suppressor Proteins; Down-Regulation; Embryonic Development; Phosphoproteins; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Trans-Activators; Animals; Humans; Protein Isoforms; Receptors, Calcitriol; Neoplasm Invasiveness; Gene Silencing; Transcription Factors

The p63 transcription factor has a pivotal role in epithelial morphogenesis. Multiple transcripts of the TP63 gene are generated because of alternative promoter usage and splicing. ΔNp63α is the predominant isoform of p63 observed during epithelial morphogenesis and in human cancers. Loss of ΔNp63α expression has been shown to promote invasiveness in a subset of human cancer cell lines. Here, we studied whether the regulation of VDR by ΔNp63α controls the invasiveness of an epidermoid cancer cell line. We demonstrate that VDR expression is induced by all p63 isoforms, including ΔNp63α. Endogenous ΔNp63α protein was observed to bind to the VDR promoter, and silencing of endogenous ΔNp63α resulted in diminished VDR expression. Although silencing of p63 inhibits VDR expression leading to an increase in cell migration, overexpression of p63 or VDR results in reduced cell migration as a result of increased VDR expression. Therefore, it is conceivable that p63 inhibits cell invasion by regulating VDR expression. Finally, we observed that expression of p63 and VDR overlaps in the wild-type mouse skin, but a reduced or complete absence of VDR expression was observed in skin from p63-null mice and in p63-null mouse embryonic fibroblasts. In conclusion, we demonstrate a direct transcriptional regulation of VDR by ΔNp63α. Our results highlight a crucial role for VDR in p63-mediated biological functions.