New discoveries about tumor-suppressing protein could help to reduce treatment side effects
Researchers at the Stanford University School of Medicine have untangled two distinct ways in which a common, naturally occurring "tumor-suppressor" protein works. The separation of these two functions which can have quite different consequences could enhance efforts to develop treatment approaches that mitigate the sometimes-devastating side effects of radiotherapy and chemotherapy.
The protein, p53, is mutated or missing in more than half of all human cancers, and most cancers involve at least some compromise in its function.
Cancer is caused by two categories of mutations: those that activate oncogenes, whose protein products drive cells into overzealous replication, and those that disable tumor-suppressor genes, which code for proteins that sense this abnormal behavior and put the brakes on it.
"We knew that p53 responds to two different types of signals: DNA damage and oncogene activity," said Laura Attardi, PhD, associate professor of radiation oncology and of genetics. "We wanted to know if p53 responds to both in the same way." Attardi is senior author of a study to be published May 13 in Cell that throws light on crucial molecular details about how p53 works.
It is widely understood that p53 can temporarily or permanently shut down cell division in response to either acute damage to a cell's DNA or biochemical signals within a cell that suggest it's prone to becoming a cancer cell. In extreme cases, p53 convincingly counsels the cell to commit suicide, thereby preventing the possibility of a tumor arising.
Attardi and her colleagues created bioengineered mice in which various parts of p53 were incapacitated. This allowed them to determine which genes are activated by different parts of the protein, and to show that p53's aggressive DNA-damage response and its gentler tumor-suppression response are separable functions.
"We've determined, for the first time, that the gene expression program p53 requires in its tumor-suppression role is distinct from that which it requires in the context of acute DNA damage," Attardi said. "Separating these responses may allow the identification of ways to inhibit the detrimental effects of radiotherapy and chemotherapy both of which damage DNA without putting a patient at risk for developing new tumors."
While most tumors lack a working p53 protein, radiotherapy and chemotherapy activate the p53 present in healthy tissues, producing serious side effects by destroying cells in the gastrointestinal tract, blood, hair follicles and brain. That's because these treatments cause profound DNA damage, a trigger for p53 action.
It's known that p53 is a transcription factor: a protein that can regulate the production of numerous other proteins inside a cell. According to scientists, p53 recognizes and perches upon a particular DNA sequence found near large numbers of genes. Once p53 has seated itself near such a gene, two different regions of the protein, called TAD1 and TAD2, can serve as landing beacons that attract mammoth molecular copying machines to the gene a key early step in protein generation.
But the response is very different depending on which of the two beacons, TAD1 or TAD2, is calling in the copying machinery.
Attardi's group used bioengineered mice in which TAD1, TAD2 or both had been disabled by mutations. This allowed the investigators to show that these two beacons flag different sets of genes.
The genes that TAD1 turns on are the ones involved in p53's show-stopping response to DNA-damage. More than 100 such genes had already been identified.
But when the investigators disabled TAD1 while leaving TAD2 intact, they were able to unmask a set of 50 or so genes turned on by TAD2. These genes, the team showed, mediate p53's ability to stimulate cells' somewhat more nuanced tumor-suppression response, which shuts down a cell only upon sensing oncogene activity, a more direct sign of potential cancer than mere DNA damage.
"When we treated the TAD1-disabled mice with high-dose radiation, they didn't suffer the DNA-damage-induced side effects that we saw in wild-type mice," said the study's lead author, Colleen Brady, a PhD student in Attardi's lab. "But TAD1-disabled mice were resistant to tumor development."
"This is an important advance," said molecular biologist and oncologist Arnold Levine, PhD, a professor at the Institute of Advanced Studies in Princeton, N.J. "The team has uncovered half of what the biggest player in human cancers does." Levine, who didn't participate in the study but is familiar with it, is one of three scientists credited for p53's discovery in 1979.
The finding that p53 can suppress tumors, even when the part of it that shuts down cells in response to DNA damage has been disabled, holds significant implications for therapy. If the two distinct activities of p53 in healthy cells can be decoupled say, by a drug impairing TAD1's function but sparing TAD2's it might be possible to avoid the massive healthy-cell die-off responsible for nausea, hair loss, immune deficiency and nerve damage that usually occur during radiotherapy or chemotherapy, without promoting new tumor development. Disabling p53's TAD1 region would allow cells that have sustained DNA damage in the course of these therapies to live to another day, but TAD2's still-intact tumor-suppressor function in those otherwise normal cells would guard against those cells becoming cancer cells.
Provided by Stanford University Medical Center
- Effect of mutant p53 stability on tumorigenesis and drug design May 15, 2008 | not rated yet | 0
- Stabilizing cancer-fighting p53 can also shield a metastasis-promoter May 22, 2008 | not rated yet | 0
- Discovery Raises Questions About Some Therapies Designed to Treat Half of all Human Cancers Apr 09, 2007 | not rated yet | 0
- Restoring the gene for cancer protein p53 slows spread of advanced tumors Nov 24, 2010 | not rated yet | 0
- New drug shrinks cancer in animals, study shows Apr 06, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be villous adenoma in colon, if there are no villi there
14 hours ago As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
- More from Physics Forums - Medical Sciences
More news stories
(HealthDay)—The American Cancer Society, which is celebrating on Wednesday a century of fighting a disease once viewed as a death sentence, is making a pledge to put itself out of business.
Cancer 4 hours ago | not rated yet | 0
National Lung Screening Trial (NLST) investigators also conclude that the 20 percent reduction in lung cancer mortality with low-dose computed tomography (LDCT) versus chest X-ray (CXR) screening previously reported in the ...
Cancer 5 hours ago | not rated yet | 0
Researchers have developed a new drug delivery system that allows inhalation of chemotherapeutic drugs to help treat lung cancer, and in laboratory and animal tests it appears to reduce the systemic damage ...
Cancer 8 hours ago | not rated yet | 0 |
When turned on, the gene p53 turns off cancer. However, when existing drugs boost p53, only a few tumors die – the rest resist the challenge. A study published in the journal Cell Reports shows how: tumors that live even i ...
Cancer 8 hours ago | not rated yet | 0 |
Study leader, Professor John Mathews from the University of Melbourne said this small increase in cancer risk must be weighed against the undoubted benefits from CT scans in diagnosing and monitoring disease.
Cancer 12 hours ago | not rated yet | 0
Swiss scientists reveal the mechanism responsible for aging hidden deep within mitochondria—and dramatically slow it down in worms by administering antibiotics to the young.
9 hours ago | 4.8 / 5 (5) | 0 |
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
9 hours ago | 4 / 5 (1) | 0 |
Until now, little was scientifically known about the human potential to cultivate compassion—the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.
6 hours ago | 5 / 5 (2) | 2 |
(HealthDay)—Migraines and depression can each cause a great deal of suffering, but new research indicates the combination of the two may be linked to something else entirely—a smaller brain.
5 hours ago | 5 / 5 (1) | 0 |
A new approach for immunizing against influenza elicited a more potent immune response and broader protection than the currently licensed seasonal influenza vaccines when tested in mice and ferrets. The vaccine ...
6 hours ago | not rated yet | 0 |
In a series of lab experiments designed to unravel the workings of a key enzyme widely considered a possible trigger of rheumatoid arthritis, researchers at Johns Hopkins have found that in the most severe ...
8 hours ago | 5 / 5 (1) | 0 |