“… If you simply ask how cells with and without p53 are different, you’ll see that there are at least 1,000 genes whose expression is affected by p53 status,” said molecular biologist Laura Attardi, PhD. “So, getting to the bottom of which of those many genes are critical to tumor suppression is not a trivial question.”
Nonetheless, her team has done just that. In a paper published this week in Cancer Cell (which, intriguingly, is accompanied by a preview titled “Tumor suppression by p53: Bring in the Hippo!” and which, I subsequently was disappointed to learn, has nothing to do with hippopotamuses), the researchers identified a chain of molecules that controls tumor development and suppression.
They also found a beneficial mutation of p53 that confers even greater protection from cancer and could inform future therapies.
A Stanford Medicine press release explains:
Attardi began sorting out the puzzle by testing the effect of several individual p53 mutations in mice that were predisposed to pancreatic cancer. Any change in p53 activity typically points to trouble: Too little leaves the body susceptible to tumor growth, whereas too much can cause problems in development. But surprisingly, one of the p53 mutants actually kept the mice tumor-free longer, suggesting it was a super version of p53…
Mice that harbored the favorable mutation, which occurred in a transcriptional activation domain called TAD2, displayed longer, pancreatic cancer-free survival than mice with normal copies of the p53 gene. Attardi’s study showed that, at 400 days old, nearly 40 percent of the mice with normal p53 function had succumbed to pancreatic cancer, whereas none of the mice with the mutant form showed signs of tumor formation.
The team also found how, in this case, p53 works. Here, it controls the expression of the protein Ptpn14, which then suppresses Yap, which left to itself activates cancer-promoting genes. That confirms the important of Yap as a therapeutic target.
Next, Attandi said she plans to investigate if the p53-Ptpn14-Yap pathway is active in tissues beyond the pancreas.
Previously: Surprise discovery links cancer protein with developmental disorder, The diagnosis behind the diagnosis and Peeking into the genome of a deadly cancer pinpoints possible new treatment
Image, showing pancreas cancer in a mouse, by Ravikanth Maddipati, Abramson Cancer Center at the Univ. of Penn., NCI, NIH