PDF(Pubmed)
Abstract：
Upregulation of PRAME (preferentially expressed antigen of melanoma) has been implicated in the progression of a variety of cancers, including melanoma. The tumor suppressor p53 is a transcriptional regulator that mediates cell cycle arrest and apoptosis in response to stress signals. Here, we report that PRAME is a novel repressive target of p53. This was supported by analysis of melanoma cell lines carrying wild-type p53 and human melanoma databases. mRNA expression of PRAME was downregulated by p53 overexpression and activation using DNA-damaging agents, but upregulated by p53 depletion. We identified a p53-responsive element (p53RE) in the promoter region of PRAME. Luciferase and ChIP assays showed that p53 represses the transcriptional activity of the PRAME promoter and is recruited to the p53RE together with HDAC1 upon etoposide treatment. The functional significance of p53 activationmediated PRAME downregulation was demonstrated by measuring colony formation and p27 expression in melanoma cells. These data suggest that p53 activation, which leads to PRAME downregulation, could be a therapeutic strategy in melanoma cells. [BMB Reports 2024; 57(6): 299-304].
摘要：
PRAME（黑色素瘤优先表达的抗原）的上调与多种癌症的进展有关。包括黑色素瘤.肿瘤抑制因子p53是一种转录调节因子,其响应于应激信号而介导细胞周期停滞和细胞凋亡。这里,我们报道PRAME是一种新的p53抑制靶点。这得到了对携带野生型p53的黑素瘤细胞系和人黑素瘤数据库的分析的支持。PRAME的mRNA表达因p53过表达和使用DNA损伤剂的激活而下调，但通过p53耗竭上调。我们在PRAME的启动子区域中鉴定了p53反应元件(p53RE)。荧光素酶和ChIP分析显示p53抑制PRAME启动子的转录活性，并在依托泊苷处理后与HDAC1一起募集到p53RE。通过测量黑色素瘤细胞中的集落形成和p27表达证明了p53激活介导的PRAME下调的功能意义。这些数据表明p53激活，导致PRAME下调，可能是黑色素瘤细胞的治疗策略。
