title: Overexpression of DRAM enhances p53-dependent apoptosis.
abstract: 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.
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University , 4-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kakudo
authors.forename: Shin
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kato
authors.forename: Chikashi
authors.initials: C
authors.lastname: Ishioka
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D001343:Autophagy / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C512709:DRAM1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53
keywords: Apoptosis; DRAM; p53; super p53