Overexpression of DRAM enhances p53-dependent apoptosis.

Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive mechanisms in human tumorigenesis. Till date, "super p53" mutants exhibiting more potent ability to induce apoptosis than wild-type p53 have been reported. These super p53s may provide a clue for development of novel therapeutic targets. However, the major mechanism underlying the super p53-dependent apoptosis remains unclear. To identify critical gene(s) in this mechanism, we performed a comprehensive and comparative expression analysis in p53-null Saos-2 cells with conditional expression of wild-type p53 and S121F, which was 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, DRAM overexpression 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. Additional analysis of the mechanism of super p53-dependent apoptosis may lead to the identification of novel drug targets for cancer therapy.