Newly discovered mechanism of p53-mediated tumor suppression
p53 acts as a tumor suppressor, which is well-known in the field of cancer research. However, the mechanisms of p53-mediated tumor suppression have not been completely characterized.
A new study (A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer) now uncovers that a specific mutation in p53 boosts the protein's ability to fight cancer.
Led by researchers from Stanford University School of Medicine, University of Toronto, and The Johns Hopkins University School of Medicine, the study was published in the respected journal Cancer Cell on October 9, 2017.
The p53 gene encodes a protein that plays a role in various aspects of cellular functions. p53 has many mechanisms of anticancer function. It can facilitate DNA repair, arrest cell growth, and initiate apoptosis. These functions contribute to cellular and genetic stability, reducing cancer risk.
p53 is a DNA-binding protein and affects the expression of a large number of genes. The question is which of these genes correlates with tumor suppression.
Dr. Laura Attardi, an expert in the field of radiation oncology and genetics from Stanford University School of Medicine, and his colleagues worked together to solve this question. By analyzing pancreatic cancer development in mice that expressed p53 mutants, they discovered that one of the p53 mutants behaved as a "super-tumor suppressor."
That beneficial mutation occurred in the transcriptional activation domain (TAD) of p53. Mice carrying the mutation were better protected against pancreatic cancer compared with mice with normal p53, indicating that the mutation boosts p53's ability to suppress tumor. Importantly, the mutation did not affect embryonic development, Dr. Attardi noted.
The team also identified the pathway through which the p53 TAD2 mutant works. The mutation enhances the activation of p53, altering the activity of its target genes, including Ptpn14. p53 activates Ptpn14, which is a potential tumor suppressor, and Ptpn14 then suppresses Yap, which is an oncogene involved in cell proliferation and inhibiting apoptotic genes. This p53-Ptpn14-Yap pathway is integral to p53-mediated tumor suppression, the researchers concluded.
Taken together, the results suggest the p53-Ptpn14-Yap pathway as a mechanism of p53-mediated tumor suppression in pancreatic cancer. Whether this mechanism is present in other types of cancer requires further investigation.
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