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Published on: August 4, 2019
Divergence of the PIERCE1 expression between mice and humans as a p53 target gene
Hye Jeong Kim1, Seung Eon Lee1, Heeju Na1
1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Abstract:
PIERCE1, p53 induced expression 1 in Rb null cells, is a novel p53 target involved in the DNA damage response and cell cycle in mice. These facts prompted us to study the function of PIERCE1 with respect to p53-associated pathophysiology of cancer in humans. Unexpectedly, PIERCE1 did not respond to overexpression and activation of p53 in humans. In this study, we swapped p53 protein expression in human and mouse cells to find the clue of this difference between species. Human p53 expression in mouse cells upregulated PIERCE1 expression, suggesting that p53-responsive elements on the PIERCE1 promoter are crucial, but not the p53 protein itself. Indeed, in silico analyses of PIERCE1 promoters revealed that p53-responsive elements identified in mice are not conserved in humans. Consistently, chromatin immunoprecipitation-sequencing (ChIP-seq) analyses confirmed p53 enrichment against the PIERCE1 promoter region in mice, not in human cells. To complement the p53 study in mice, further promoter analyses suggested that the human PIERCE1 promoter is more similar to guinea pigs, lemurs, and dogs than to rodents. Taken together, our results confirm the differential responsiveness of PIERCE1 expression to p53 due to species differences in PIERCE1 promoters. The results also show partial dissimilarity after p53 induction between mice and humans.
Insights
PIERCE1 gene expression differs between humans and mice due to species-specific promoter elements. This impacts the DNA damage response and cell cycle regulation in cancer pathophysiology.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- PIERCE1 (p53 induced expression 1) is a p53 target gene involved in DNA damage response and cell cycle regulation in mice.
- Its role in human cancer pathophysiology, particularly concerning p53, remained unclear due to unexpected differential expression.
Purpose of the Study:
- To investigate the species-specific differences in PIERCE1 regulation by p53.
- To elucidate the molecular mechanisms underlying the differential responsiveness of PIERCE1 to p53 in human versus mouse cells.
Main Methods:
- Cross-species p53 protein expression swapping between human and mouse cells.
- In silico analysis of PIERCE1 promoter regions.
- Chromatin immunoprecipitation-sequencing (ChIP-seq) to assess p53 binding to the PIERCE1 promoter.
Main Results:
- Human p53 expression in mouse cells upregulated PIERCE1, indicating promoter elements are key.
- p53-responsive elements in mouse PIERCE1 promoters are not conserved in humans.
- ChIP-seq confirmed p53 enrichment at the mouse PIERCE1 promoter but not in human cells.
- Human PIERCE1 promoter shows greater similarity to non-rodent species like guinea pigs, lemurs, and dogs.
Conclusions:
- Differential responsiveness of PIERCE1 to p53 is due to species-specific differences in PIERCE1 promoter sequences.
- These findings highlight the importance of species-specific genetic elements in cancer-related gene regulation and response to p53.
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