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.

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