Nav: Home

AACR study sheds light on dark side of tumor suppressor gene, p53

April 02, 2017

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 cancer, it has a tremendous impact on tumorigenesis. Anything that regulates the p53 pathway 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 genes, 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 cells 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.
-end-


University of Colorado Anschutz Medical Campus

Related Cancer Articles:

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.
Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.
Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.