Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cold viruses point the way to new cancer therapies

17.10.2012
Salk findings on cold virus proteins may spur new cancer treatments

Cold viruses generally get a bad rap----which they've certainly earned----but new findings by a team of scientists at the Salk Institute for Biological Studies suggest that these viruses might also be a valuable ally in the fight against cancer.


Salk researchers discovered that a small protein produced by cold viruses disables large cellular machines involved in growth, replication and cancer. These proteins accomplish this by forming a three-dimensional web inside a cell's nucleus (yellow) that traps these components. The findings point the way to new ways to target and destroy tumors.

Credit: Courtesy of the Salk Institute for Biological Studies

Adenovirus, a type of cold virus, has developed molecular tools----proteins----that allow it to hijack a cell's molecular machinery, including large cellular machines involved in growth, replication and cancer suppression. The Salk scientists identified the construction of these molecular weapons and found that they bind together into long chains (polymers) to form a three-dimensional web inside cells that traps and overpowers cellular sentries involved in growth and cancer suppression. The findings, published October 11 in Cell, suggest a new avenue for developing cancer therapies by mimicking the strategies employed by the viruses.

"Cancer was once a black box," says Clodagh O'Shea, an assistant professor in Salk's Molecular and Cell Biology Laboratory, who led the study. "The key that opened that box was revealing the interactions between small DNA tumor virus proteins and cellular tumor suppressor complexes. But without knowing the structure of the proteins they use to attack cells, we were at a loss for how these tiny weapons win out over much larger tumor suppressors."

O'Shea's team studied E4-ORF3, a cancer-causing protein encoded by adenovirus, which prevents the p53 tumor suppressor protein from binding to its target genes. Known as the "guardian of the genome," p53 normally suppresses tumors by causing cells with DNA damage----a hallmark of cancer----to self-destruct. The p53 tumor suppressor pathway is inactivated in almost every human cancer, allowing cancer cells to escape normal growth controls. Similarly, by inactivating p53, the E4-ORF3 protein enables adenovirus replication in infected human cells to go unchecked.

Two years ago, O'Shea discovered that E4-ORF3 clears the way for adenovirus to proliferate by deactivating genes that help the cell defend itself against the virus. "It literally creates zip files of p53 target genes by compressing them until they can no longer be read," she explains.

E4-ORF3 self-assembles inside cells into a disordered, web-like structure that captures and inactivates different tumor suppressor protein complexes. Horng Ou, a postdoctoral researcher in O'Shea's laboratory, says E4-ORF3 is unusual. "It doesn't resemble any known proteins that assemble polymers or that function in cellular tumor suppressor pathways," he says. "Most cellular polymers and filaments form uniform, rigid chains. But E4-ORF3 is the virus's Swiss army knife----it assembles into something that is highly versatile. It has the ability to build itself into all sorts of different shapes and sizes that can capture and deactivate the many defenses of a host cell."

In collaboration with scientists from the National Center for Microscopy and Imaging Research at University of California, San Diego, led by Mark Ellisman, the center's director, O'Shea's team used new techniques to reveal the ultrastructure of the remarkable polymer that E4-ORF3 assembles in the nucleus----something that previously had proven difficult since the polymer is effectively invisible using conventional electron microscopy. "What you see is the E4-ORF3 polymer bending and weaving and twisting its way through the nucleus," she says. "It does appear to have a single repeating pattern and creates a matrix that captures several different tumor suppressors and silences p53 target genes."

Initially, E4-ORF3 forms a dimer, made up of only two subunits. In this form, E4-ORF3 largely ignores its cellular targets. The researchers theorized that when E4-ORF3 assembles into a polymer, however, it binds to tumor suppressor targets far more aggressively. To test this theory, they genetically fused E4-ORF3 polymer mutants to lamin, a cellular protein that assembles intermediate filaments that provide stability and strength to cells. They showed that the lamin-E4-ORF3 fusion protein assembled into cylinder-like superstructures in the nucleus that bind and disrupt PML, a protein complex that suppresses tumors.

The Salk findings may help scientists develop small molecules----the basis for the vast majority of current drugs----capable of destroying tumors by binding and disrupting large and complex cellular components that allow cancer cells to grow and spread. Understanding how viruses overcome healthy cells may also help scientists engineer tumor-busting viruses, which offer a new and potentially self-perpetuating cancer therapy. Such modified viruses would destroy only cancer cells, because they could only replicate in cells in which the p53 tumor suppressor has been deactivated. When a cancer cell is destroyed it would release additional copies of the engineered viruses, which would seek out and kill remaining cancer cells that have spread throughout the body.

Engineering these viruses requires disabling the ability of the E4-ORF3 protein to inactivate p53 in healthy cells----otherwise, the virus could destroy healthy cells as well as cancer cells. At the same time, E4-ORF3 has certain important functions in allowing the virus to replicate in the first place, so it can't be completely removed from the virus's arsenal. Thus, the Salk researcher's work on understanding the protein's precise structure, functions and interactions is crucial to engineering viruses in which E4-ORF3's abilities have been precisely modified.

Other researchers on the study were Witek Kwiatkowski, Katherine Blain, Hannah Land, Conrado Soria, Colin Powers, James Fitzpatrick, Jeff Long and Senyon Choe from the Salk Institute; Thomas Deerinck, Andrew Noske, Xiaokun Shu and Roger Tsien of the University of California, San Diego; and Andrew May of Fluidigm.

The work was supported by the National Institutes of Health, American Cancer Society, Sontag Foundation, the Arnold and Mabel Beckman Foundation, and Anna Fuller Foundation.

Andy Hoang | EurekAlert!
Further information:
http://www.salk.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>