Suppressor To Prevent Pancreatic Cancer

Honor Whiteman recently wrote about a new study confirming that not all gene mutations are bad, after discovering a mutation that appears to give a known tumor suppressor gene a boost against pancreatic cancer.  They found that mice possessing a specific mutation in the p53 gene were significantly less likely to develop pancreatic tumors when compared with those that did not have this gene mutation.

Laura Attardi, Ph.D. of the Department of Genetics at the Stanford University School of Medicine in California, senior study author along with her colleagues, reported the findings in the journal Cancer Cell.  The p53 gene is referred to as tumor protein p53 that protects against tumor development.  When located on chromosome 17 the gene encodes the p53 protein.  The p53 protein triggers DNA repair, apoptosis (programmed cell death) and cell cycle arrest in order to halt the growth and replication of cells with damaged DNA, helping to prevent tumors from developing.  The study has identified one that may have the opposite effect, making the p53 gene a “super tumor suppressor.”

One mutation that is situated in a transcriptional activation domain and known as TAD2, appeared to halt pancreatic tumor development.  About 40% of mice with normal p53 functioning developed pancreatic cancer but those mice with the p53-TAD2 mutation did not develop the disease.    Even though low p53 activity can lead to cancer development, too much p53 can interfere with embryonic development.  The p53-TAD2 mutation manages to strike a good balance between the two.  This mutant his a sweet spot, according to Dr. Attardi.  The embryos can make it through development without obvious effects, and adult mice show greatly enhanced resistance to tumor growth.

They found the mutation activates a protein called Ptpn14 that suppresses a protein called Yap and prevents cells from becoming cancerous.  They conducted an analysis of human cancer genomic data and found that Yap activity increases in response to other p53 gene mutation and provides further evidence that the Yap protein is involved in cancer development.  They believe the p53-Ptpn14-Yap axis is a central mechanism.  It is now believed that a discovery has been made that could lead to new cancer treatments.  Yap is a very potent oncogene and the study suggests the focus should be on developing Yap inhibitors for tumors where p53 is gone.  They plan to investigate if the p53-TAD2 mutation can halt the development of other cancers.

Fredda Branyon