p53 protein is encoded by TP53 gene in humans. It’s also known as tumor suppressor.
P53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of angiogenesis.
In its anti-cancer role, p53 works through several mechanisms:
- It can activate DNA repair proteins when DNA has sustained damage.
- It can induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).
- It can initiate apoptosis, the programmed cell death, if DNA damage proves to be irreparable.
If TP53 gene is damaged then the ability to fight cancer is severly damaged in such people. Cancer cells typically inactivate the TP53 gene so they can freely multiply the cancer cells.
A representation of a complex between DNA and the protein p53.
Image: Thomas Splettstoesse
Knowing p53’s critical role in controlling cancer, researchers have been trying to develop drugs that restore the protein’s function, in hopes of re-establishing the ability to suppress tumor growth. One such drug is now in clinical trials.
In a new study that highlights a possible limitation of such drugs, MIT cancer biologists show that restoring p53’s function in mice with lung cancer has no effect early in tumor development, but restoring the function later on could prevent more advanced tumors from spreading throughout the body.
The findings, reported in the Nov. 25 issue of Nature, suggest that drugs that restore p53 function could help prevent aggressive lung cancers from metastasizing, though they might spare benign tumor cells that could later turn aggressive. “Even if you clear the malignant cells, you’re still left with benign cells harboring the p53 mutation,” says David Feldser, lead author of the paper and a postdoctoral fellow at the David H. Koch Institute for Integrative Cancer Research at MIT.
In the new Nature study, the MIT researchers studied mice that are genetically engineered to develop lung tumors shortly after birth. Those mice also have an inactive form of the p53 gene, but the gene includes a genetic “switch” that allows the researchers to turn it back on after tumors develop.
At first, the researchers turned on p53 in mice that were four weeks old and had developed tumors known as adenomas, which are benign. To their surprise, restoring p53 had no effect on the tumors.
Next they turned on p53 in another group of tumor-prone mice, but they waited until the mice were 10 weeks old. At this point, their tumors had progressed to adenocarcinomas, a malignant type of cancer. In these mice, turning on p53 cleared the malignant cells, but left behind cells that had not become malignant.
This suggests that the p53 signaling pathway is recruited only when there is a lot of activity from other cancer genes. In benign tumors, there is not enough activity to engage the p53 system, so restoring it has no effect on those tumors. In the malignant tumor cells, reactivated p53 eliminates cells with too much activity in a signaling pathway involving mitogen-activated protein kinase (MAPK), which is often overactive in cancer cells, leading to uncontrolled growth.
In this study, the researchers restored normal levels of p53, but a p53-activating drug would likely generate much higher levels of the protein, says Geoffrey Wahl, a professor at the Salk Institute. With elevated p53, “it might be that you get a more significant response than what was observed here,” he says.
The MIT researchers are now looking for drugs that reactivate mutant forms of p53, and also plan to study whether tumors that have metastasized would be vulnerable to p53 restoration.