Identification of dihydropyrimidinase-related protein 4 as a novel target of the p53 tumor suppressor in the apoptotic response to DNA damage.
The p53 tumor suppressor gene, which is frequently mutated in a wide variety of tumors, plays an important role in maintaining genomic integrity. Following genotoxic insults, the protein level of p53 is increased, and p53 functions as a sequence-specific transcription factor that regulates the expression of downstream target genes required for cell cycle arrest, DNA repair or apoptosis. However, the mechanism for p53-inducible apoptosis remains largely unclear. To search novel downstream targets of p53 on apoptosis, we had carried out microarray analysis. We identified dihydropyrimidinase-related protein (DPYSL) 4 gene, which was upregulated by overexpressing p53 in p53-deficient cells. Both mRNA and protein expressions of DPYSL4 were specifically induced by anticancer agents in p53-proficient cells. Further analyses demonstrated that DPYSL4 was a direct target for p53. We also found that genotoxic-induced apoptosis was repressed in cells silenced for DPYSL4. These findings indicate that DPYSL4 is a novel apoptosis-inducible factor controlled by p53 in response to DNA damage.
Kimura
Junko
J
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Kudoh
Takuya
T
Miki
Yoshio
Y
Yoshida
Kiyotsugu
K
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004249:DNA Damage; D016158:Genes, p53; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry
C485780:DPYSL4 protein, human; C405926:Dpysl4 protein, mouse; D009419:Nerve Tissue Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin