Analysis of gain-of-function mechanisms of mutant p53 and identification of novel target for cancer therapy.

到目前为止，一些功能获得突变体的“超级P53”突变体已被报道为比野生型P53具有更强的诱导凋亡能力的突变体。超级p53s可能为开发新的治疗靶点提供线索，但超p53依赖的细胞凋亡的主要机制尚不清楚。为了确定该机制中的关键基因(S)，我们在野生型p53和S121F条件表达的P53缺失的SAOS-2细胞中进行了全面的比较分析，S121F是先前报道的P53超突变。我们发现损伤调节自噬调节器(DRAM)是S121F比野生型P53上调更多的基因之一。虽然DRAM的敲除不足以降低S121F诱导凋亡的能力，但DRAM的过表达以野生型P53依赖的方式增强了S121F的诱导凋亡能力。在这里，我们表明DRAM是促进P53依赖的细胞凋亡的重要基因。

So far, "super p53" mutants of several gain-of-function mutants have been reported as mutants exhibiting more potent ability to induce apoptosis than wild-type p53. The super p53s may provide a clue for development novel therapeutic targets, but the major mechanism underlying the super p53-dependent apoptosis remains unclear. To identify critical gene(s) in the mechanism, we performed comprehensive and comparative expression analysis in p53-null Saos-2 cells with conditional expression of wild-type p53 and S121F, previously reported as a super p53 mutant. We identified damage-regulated autophagy modulator (DRAM) as one of the genes that were more upregulated by S121F than wild-type p53. Although knockdown of DRAM was not sufficient for reducing the ability of S121F to induce apoptosis, overexpression of DRAM enhanced the ability in a wild-type p53-dependent manner. Here, we show that DRAM is an important gene for the enhancement of p53-dependent apoptosis.