Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
Mol Cancer Res. 2009 Dec;7(12):2031-9. doi: 10.1158/1541-7786.MCR-08-0501. Epub 2009 Dec 1.
We have previously characterized how p53 family proteins control the transcriptional regulation of the platelet-derived growth factor beta-receptor (PDGFRB) and found that DeltaNp73alpha, 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 DeltaNp73. 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, DeltaNp73 was found constitutively bound to the PDGFRB promoter, and silencing of DeltaNp73 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 DeltaNp73 from the PDGFRB promoter and recruited p53 and p73, leading to binding of histone deacetylase 4. These results suggest a direct role of DeltaNp73 in the constantly enhanced PDGFRB expression seen in tumors.
我们之前已经描述了 p53 家族蛋白如何控制血小板衍生生长因子β受体（PDGFRB）的转录调控，并且发现 DeltaNp73alpha 通过对 p53 和 p73 的显性负调控作用，可以上调 PDGFRB 启动子活性。在这里，我们报告 PDGFRB 的调节在两种神经母细胞瘤细胞系中存在差异，这与 DeltaNp73 的作用有关。我们发现 PDGFRB 在 IMR-32 细胞中高度表达，而在 SH-SY5Y 细胞中，血清刺激不会下调 PDGFRB 的表达，而在 IMR-32 细胞中则不会。在 IMR-32 中，DeltaNp73 被发现与 PDGFRB 启动子持续结合，沉默 DeltaNp73 导致 PDGFRB 启动子活性受到抑制，以及 PDGFRB 蛋白表达减少。然而，已知能够稳定和激活 p53 和 p73 的抗癌药物顺铂不仅在 SH-SY5Y 中，而且在 IMR-32 中也下调了 PDGFRB 的表达。染色质免疫沉淀显示，顺铂将 DeltaNp73 从 PDGFRB 启动子上移除，并招募了 p53 和 p73，导致组蛋白去乙酰化酶 4 的结合。这些结果表明 DeltaNp73 在肿瘤中持续增强的 PDGFRB 表达中起着直接作用。
