Dysregulation of platelet-derived growth factor beta-receptor expression by DeltaNp73 in neuroblastoma

We have previously characterized how p53 family proteins control the transcriptional regulation of the platelet-derived growth factor β-receptor (PDGFRB) and found that ΔNp73α, acting dominant-negatively to p53 and p73, can upregulate PDGFRB promoter activity. Here, we report that PDGFRB regulation differs between two neuroblastoma cell lines, correlating with the actions of ΔNp73. We found that PDGFRB was highly expressed in IMR-32 cells, and serum stimulation of IMR-32 cells did not downregulate PDGFRB expression, as seen in SH-SY5Y cells. In IMR-32, ΔNp73 was found constitutively bound to the PDGFRB promoter, and silencing of ΔNp73 resulted in repression of PDGFRB promoter activity as well as decreased PDGFRB protein expression. However, the anticancer drug cisplatin, known to stabilize and activate p53 and p73, downregulated PDGFRB expression not only in SH-SY5Y but also in IMR-32. Chromatin immunoprecipitation showed that cisplatin removed ΔNp73 from the PDGFRB promoter and recruited p53 and p73, leading to binding of histone deacetylase 4. These results suggest a direct role of ΔNp73 in the constantly enhanced PDGFRB expression seen in tumors. (Mol Cancer Res 2009;7(12):2031–9)