Study sheds light on dark side of tumor suppressor gene, p53

April 3, 2017 by Garth Sundem, CU Anschutz Medical Campus
Tamara Terzian, Ph.D., and colleagues detail the genes that regulate p53. Credit: University of Colorado Cancer Center

The gene p53 is the most commonly mutated gene in cancer - it is p53's job to monitor cells for DNA damage and to mark damaged cells for destruction and so cancer cells with mutated DNA must disable p53 before it disables them. However, there is a second, darker side to p53. While intact or "wild type" p53 is a tumor suppressor, mutated p53 can itself become an oncogene, driving the progression of the disease. A University of Colorado Cancer Center study presented today at the American Association for Cancer Research (AACR) Annual Meeting 2017 picks apart the dark side of this gene, the mutated, oncogenic form of p53, to show that other genes, Mdm2 and now for the first time Mdm4, keep mutated p53 in check.

"Because p53 is the most frequently mutated gene in , it has a tremendous impact on tumorigenesis. Anything that regulates the has an importance in tumor development - and potentially for therapy," says senior author Tamara Terzian, PhD, investigator at the CU Cancer Center and assistant professor at the Gates Center for Regenerative Medicine on the University of Colorado Anschutz Medical Campus.

In healthy cells, Mdm2 and Mdm4 keep p53 at low levels; studies have shown that nixing these proteins results in a spike in p53 and the destruction of the cell. Commonly, DNA damage - either oncogenic mutations or other non-cancer stressors - results in high p53 and cell death. And, also commonly, cancer evades this blockade by mutating p53, keeping its levels artificially low despite high DNA damage.

But there is another storyline to p53 and cancer. In this second story, cancer mutates p53 and uses this new form to drive its growth directly. Now cancer would like to turn up this mutated form of p53. And now doctors, instead of wishing that healthy p53 would spike in response to oncogenic DNA, wish that mutated p53 would go away.

"When you take out either of these two , Mdm2 or Mdm4, mutated p53 is elevated and mice die earlier of mutant-p53-driven cancers," Terzian says. However, Terzian's study also shows cooperation between 2 and 4. "When you knock down either, you boost the level of mutant p53, and when you take them both out, it kind of goes through the roof," she says.

Therapies now in clinical trials attempt to force cancer-causing mutant p53 back into the mold of cancer-killing healthy p53, for example, because many hold both mutant and wild type p53, "by activating the wild type or depleting the mutant or making the mutant into the wild type," Terzian says.

"We want to know both what regulates p53 and what are its target genes," Terzian says. "And in the case of mutant p53 we are not talking about a homogenous actor - we have multiple mutations and each one makes a protein of its own; each has a mind of its own. Wild type is just one form, but mutant proteins have endless possibilities. Asking questions about these possibilities expands the horizon."

The horizon is becoming clearer - wild type p53 kills cancer and mutant p53 causes cancer. Both types are suppressed by Mdm2 and Mdm4. The challenge is to manipulate these proteins or other actors in the chain of signaling that extends from these proteins, at the right time in the right patients.

"By understanding how mutant p53 proteins are regulated, we increase the likelihood of developing a successful therapeutic strategy to treat tumors," says Terzian.

Explore further: Cancer drug trial success

Related Stories

Cancer drug trial success

June 6, 2016
The successful results of a University of Liverpool led drug trial aimed at developing new therapeutic approaches to cancer have been presented at two American medical conferences.

Research shows molecular, protein targeting therapies may be best treatment for certain lung cancer

January 7, 2014
University of Cincinnati (UC) Cancer Institute researchers have found that using therapies specifically targeting the molecular profile of non-small-cell lung cancer with the mutated cancer-causing protein KRas is the most ...

Scientists discover new therapeutic target for lung cancer driven by KRAS

July 28, 2016
UT Southwestern Medical Center researchers have identified a new way to target lung cancer through the KRAS gene, one of the most commonly mutated genes in human cancer and one researchers have so far had difficulty targeting ...

Recommended for you

Cancer risk associated with key epigenetic changes occurring through normal aging process

February 22, 2018
Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration ...

Putting black skin cancer to sleep—for good

February 22, 2018
An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes ...

NEJM reports positive results for larotrectinib against TRK-fusion cancer

February 22, 2018
In 2013, the labs of University of Colorado Cancer Center investigator Robert C. Doebele, MD, PhD, and Dana-Farber Cancer Institute investigator Pasi A. Jänne, MD, PhD reported in Nature Medicine the presence of TRK gene ...

New therapeutic gel shows promise against cancerous tumors

February 21, 2018
Scientists at the UNC School of Medicine and NC State have created an injectable gel-like scaffold that can hold combination chemo-immunotherapeutic drugs and deliver them locally to tumors in a sequential manner. The results ...

Five novel genetic changes linked to pancreatic cancer risk

February 21, 2018
In what is believed to be the largest pancreatic cancer genome-wide association study to date, researchers at the Johns Hopkins Kimmel Cancer Center and the National Cancer Institute, and collaborators from over 80 other ...

Similarities found in cancer initiation in kidney, liver, stomach, pancreas

February 21, 2018
Recent research at Washington University School of Medicine in St. Louis demonstrated that mature cells in the stomach sometimes revert back to behaving like rapidly dividing stem cells. Now, the researchers have found that ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.