Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Findings suggest need for new view of p53 cancer protein’s interaction with DNA

15.07.2004


Perhaps the most commonly mutated of all cancer-linked genes is the gene for a tumor suppressor called p53. Scientists estimate that at least half of human cancers involve mutant p53. In the course of performing its regular duties, the normal p53 protein binds to DNA, and a number of cancer-linked p53 mutations affect the DNA-binding region of the p53 protein.

But precisely how does the p53 protein bind to DNA? Since DNA binding is crucial to the protein’s usual function, the answer to this question is key to drug development efforts aimed at countering the effects of p53 mutations. Scientists thought that they had a good window on the p53 protein’s interactions with DNA from structural studies that showed a single copy of the protein bound to DNA in a particular conformation.

Now a team of researchers from The Wistar Institute, the Memorial Sloan-Kettering Cancer Center, and the Howard Hughes Medical Institute report on new structural studies that will likely lead scientists to revise their views of how the p53 protein binds to DNA. The findings appear in today’s issue of the journal Structure.



"Mutant forms of p53 in human cancer are often defective in their binding to DNA, and a number of groups are trying to develop drugs that might treat cancer by restoring the DNA-binding activity of these mutants," says Thanos D. Halazonetis, D.D.S., Ph.D., associate professor in the molecular and cellular oncogenesis program at Wistar and senior author on the Structure study. "A full understanding of precisely how p53 binds to DNA is essential for this work, however. Our studies suggest that we may need to adjust the existing model of how p53 binds to DNA."

Taking advantage of the fact that evolution commonly conserves vital proteins from species to species, Halazonetis and his colleagues solved the structure of the binding region of a protein called Cep-1 from C. elegans, a roundworm, and compared it to the binding region of human p53. Their assumption was that, because the Cep-1 protein and human p53 bind to nearly identical DNA sequences in their respective genomes, their structures would also be quite similar. What they found instead was an important structural difference in Cep-1 that would prevent it from binding to its DNA sequence in the same way p53 has been shown to do to its.

At first glance, these results would seem to be more confusing than helpful. Halazonetis believes, however, that resolution of the apparent conflict lies in remembering that the p53 protein in its natural cellular environment assembles itself into tetramers – symmetrical molecules made up of four copies of the p53 protein. Halazonetis hypothesizes that both Cep-1 and p53 exist primarily as tetramers under normal circumstances and that it is in that form that they bind their respective, but nearly identical, DNA sequences. Small structural changes brought about in the formation of the tetramers would allow human p53 and Cep-1 to adopt identical conformations and would therefore explain how these two proteins recognize the same DNA sequence.

"This would have important implications for the development of anti-cancer drugs targeting the activity of p53, because these drug development efforts will require a very detailed understanding of how p53 binds DNA," Halazonetis says.

In addition to senior author Halazonetis, the other Wistar-based authors on the Structure study include first author Yentram Huyen, a University of Pennsylvania graduate student, and Elena S. Stavridi, Ph.D. The other coauthors are Philip D. Jeffrey at Memorial Sloan-Kettering Cancer Center; Nikola P. Pavletich, at the Howard Hughes Medical Institute and Memorial Sloan-Kettering Cancer Center; and W. Brent Derry and Joel H. Rothman at the University of California, Santa Barbara (Derry is currently at The Hospital for Sick Children, Toronto).

| EurekAlert!
Further information:
http://www.wistar.upenn.edu

More articles from Life Sciences:

nachricht Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

Im Focus: Newly proposed reference datasets improve weather satellite data quality

UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration

"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...

Im Focus: Repairing defects in fiber-reinforced plastics more efficiently

Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.

Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Multiregional brain on a chip

16.01.2017 | Power and Electrical Engineering

New technology enables 5-D imaging in live animals, humans

16.01.2017 | Information Technology

Researchers develop environmentally friendly soy air filter

16.01.2017 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>