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 Research team creates new possibilities for medicine and materials sciences
22.01.2018 | Humboldt-Universität zu Berlin

nachricht Saarland University bioinformaticians compute gene sequences inherited from each parent
22.01.2018 | Universität des Saarlandes

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Thanks for the memory: NIST takes a deep look at memristors

22.01.2018 | Materials Sciences

Radioactivity from oil and gas wastewater persists in Pennsylvania stream sediments

22.01.2018 | Earth Sciences

Saarland University bioinformaticians compute gene sequences inherited from each parent

22.01.2018 | Life Sciences

VideoLinks Wissenschaft & Forschung
Overview of more VideoLinks >>>