Cancer researchers have known since the 1980s that p53 plays a critical role in protecting cells from becoming cancerous. P53 is defective in about half of all human cancers; when it functions correctly, it appears to suppress tumor formation by preventing cells with cancer-promoting mutations from reproducing.
Knowing p53's critical role in controlling cancer, researchers have been trying to develop drugs that restore the protein's function, in hopes of reestablishing the ability to suppress tumor growth. One such drug is now in clinical trials.
The findings of this new study 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.
However, such drugs are still worth pursuing because they could prolong the life of the patient, says Feldser, who works in the lab of Koch Institute Director Tyler Jacks, senior author of the paper. The research was funded by the Howard Hughes Medical Institute.
P53 is known to control the cell cycle, which regulates cell division. In particular, the protein stops a cell from dividing when its DNA is damaged. P53 then activates DNA repair systems, and if the damage proves irreparable, it instructs the cell to commit suicide.
Without p53, cells can continue dividing even after acquiring hazardous mutations. Eventually, after a cell accumulates enough mutations, it becomes cancerous. Cancer biologists believe that sustained inactivation of p53 and other tumor suppressors is necessary for cancers to become advanced.
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.
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.
Source: "Stage-specific sensitivity to p53 restoration during lung cancer progression," by David M. Feldser, Kamena K. Kostova, Monte M. Winslow, Sarah E. Taylor, Chris Cashman, Charles A. Whittaker, Francisco J. Sanchez-Rivera, Rebecca Resnick, Roderick Bronson, Michael T. Hemann, and Tyler Jacks. Nature, 25 November 2010.
Funding: The Howard Hughes Medical Institute
Jen Hirsch | EurekAlert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences