Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New way to control protein activity could lead to cancer therapies

30.09.2008
Investigators at the Stanford University School of Medicine have found a way to quickly and reversibly fine-tune the activity of individual proteins in cells and living mammals, providing a powerful new laboratory tool for identifying — more precisely than ever before — the functions of different proteins.

The new technique also could help to speed the development of therapies in which cancer-fighting proteins are selectively delivered to tumors.

The procedure, described in a Nature Medicine paper to be published online Sept. 28, appears to be broadly applicable to efforts to understand the biological roles of all kinds of proteins, including those that are secreted by cells. This category includes many potent intercellular signaling proteins that can influence the immune system, for example by attracting its attention to an existing tumor.

"We have yet to find a protein the system doesn't work with," said senior author Steve Thorne, PhD, an assistant professor at the University of Pittsburgh who was involved in the work while a research associate at Stanford. The work was conducted under the direction of Chris Contag, PhD, associate professor of pediatrics, of radiology and of microbiology and immunology; and Tom Wandless, PhD, assistant professor of chemical and systems biology.

This technique, which was tested in mice, involves pairing specially bioengineered proteins with a drug, aptly named Shield-1, that prevents the proteins from being degraded.

This approach stands in contrast to current ways of learning about proteins' functions, which are largely based on impeding a cell's production of the protein. Unfortunately, that cellular process can be slow and cumbersome, meaning that scientists get a sluggish response to such manipulations. In addition, current methods to perturb protein function are either irreversible — once a protein's production is knocked out, it can't be turned back on — or difficult to execute.

The new technique, instead, influences the level of speed with which the protein is broken down—a much faster process than its production. Moreover, it is reversible and works like a dimmer switch for an overhead light. The rate of a protein's degradation — and, thus, the level of its biological activity — can be increased or decreased by supplying more or less of Shield-1, permitting scientists to study the biological effects of slightly increasing or diminishing a protein's activity inside a cell over short time frames: for example, during a particular period in an organism's development.

The Stanford team succeeded in controlling levels of proteins by a relatively simple method pioneered by Wandless and his then-graduate student, Laura Banaszynski, PhD. They created special, bioengineered versions of several different proteins, in each case altering the protein by adding a small extra piece that didn't interfere with its biological function, but flagged it for rapid degradation. This degradation can be halted in its tracks, however, by Shield-1, which binds to the bioengineered protein, shielding it from destruction by the cell's breakdown machinery. The drug thus can enhance the bioengineered protein's intracellular concentration and activity; withdrawing the drug has the opposite effect.

"The process is tunable, and fast. As soon as you remove the drug, you affect the degradation time of the protein," said Mark Sellmyer, a graduate student at the School of Medicine, who shares lead authorship of the study with Banaszynski.

The degradation-vulnerable bioengineered proteins were each produced by attaching the gene coding for a protein to another DNA sequence coding for the small extra piece that flags the protein for rapid degradation. The scientists then inserted the altered gene into a virus capable of infecting cells and introducing the altered gene into the cells' genomes.

In experiments demonstrating for the first time that the new technique can be used to effectively regulate a physiologically active protein in live mice, cultured tumor cells were grafted under the skin of immunologically impaired mice. As expected, the mice developed numerous tumors. The investigators had altered these cultured tumor cells so that they produced a degradation-prone bioengineered version of the protein IL-2 that, when secreted by cells, sends potent signals drawing the immune system's attention to those cells. When these altered tumor cells were grafted subcutaneously in the absence of Shield-1, the tumors grew just as before.

But if the tumor cells were first pretreated with Shield-1 they secreted IL-2, preventing any initial tumor growth. If Shield-1 was withheld at first and then administered to the mice five days after the grafts, tumors that had developed in those first few days regressed. By day 14, the tumors were gone.

Another set of experiments employed a mutant virus that had been previously developed by Thorne as a cancer therapy. The investigators inserted the gene for a bioengineered, degradation-prone form of a cell-killing protein into the specialized virus. They then administered it intravenously to live, tumor-bearing mice. When no Shield-1 was provided, the tumor growth was only slightly diminished. But if Shield-1 was supplied three days after infection, when the virus had established a solid foothold in the tumors but been cleared from normal cells, tumors were completely eradicated in 90 percent of the mice. Meanwhile, normal cells were spared the substance's lethal effects.

Bruce Goldman | EurekAlert!
Further information:
http://www.stanford.edu
http://mednews.stanford.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: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

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....

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

A smart safe rechargeable zinc ion battery based on sol-gel transition electrolytes

20.07.2018 | Power and Electrical Engineering

Reversing cause and effect is no trouble for quantum computers

20.07.2018 | Information Technology

Princeton-UPenn research team finds physics treasure hidden in a wallpaper pattern

20.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>