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 Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Global study of world's beaches shows threat to protected areas

19.07.2018 | Earth Sciences

New creepy, crawly search and rescue robot developed at Ben-Gurion U

19.07.2018 | Power and Electrical Engineering

Metal too 'gummy' to cut? Draw on it with a Sharpie or glue stick, science says

19.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>