PIERCE1, p53 induced expression 1 in Rb null cells, is a novel p53 target in mice involved in DNA damage response and cell cycle. Sensitization to DNA damage by PIERCE1 depletion in mice prompted us to study PIERCE1 function in respect to p53 associated pathophysiology such as DNA damage response, cell cycle, and cancer in humans. Unexpectedly, PIERCE1 did not respond to the overexpression and cisplatin-mediated activation of p53 in humans, regardless of normal and cancerous status of the cells. In mouse cells, the expression of human p53 could upregulate PIERCE1 expression, suggesting that p53-responsive elements on PIERCE1 promoter are crucial, but not p53 protein itself. Indeed, in silico analyses of PIERCE1 promoters revealed that p53-responsive elements are not conserved between mice and humans. Furthermore, analyses of chromatin immunoprecipitation sequencing showed approximately 80% lower binding affinity of p53 against PIERCE1 promoter in human, compared with mouse cells. Further promoter analyses suggested that human PIERCE1 promoter is more similar to guinea pigs, lemurs, and dogs than rodents. Taken together, our results demonstrate differential responsiveness of PIERCE1 expression to p53 due to species difference of PIERCE1 promoters and show partial dissimilarity upon p53 induction between mice and humans.