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Cold Virus Proteins Give New Clues For Cancer Therapy

A new study by scientists in the US suggests cold viruses may prove to be surprisingly valuable allies in the fight against cancer. The findings, published on 12 October in Cell, reveal how small proteins in a type of cold virus, hijack molecular mechanisms inside healthy cells, silence cancer-fighting genes and form sprawling 3D polymer webs that overpower cellular agents of growth and cancer suppression.

Study leader Clodagh O'Shea is an assistant professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies in La Jolla, California. In a press statement she explains how we once viewed cancer as a "black box", and then discovered a "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," says O'Shea. E4-ORF3, a Cancer-Causing "Swiss Army Knife" Protein The researchers decided to investigate E4-ORF3, a cancer-causing protein encoded by adenovirus, a large group of DNA viruses that includes cold viruses.

One of the ways E4-ORF3 promotes cancer is by preventing the p53 tumor suppressor protein from binding to its target genes. O'Shea's lab discovered this about two years ago.

P53 is known as the "guardian of the genome" for its important role in tumor suppression. It causes cells with damaged DNA, a distinguishing feature of cancer, to commit cell suicide ("apoptosis"). That pathway is inactivated in nearly every known human cancer, allowing cancer cells to multiply unchecked.

Also, by silencing p53, the E4-ORF3 protein allows adenovirus to replicate freely in infected human cells.

O'Shea says E4-ORF3 "literally creates zip files of p53 target genes by compressing them until they can no longer be read".

The protein "self-assembles" inside cells as a disordered, 3D web that snares and inactivates various tumor suppressor protein complexes.

This is unusual for a polymer-forming protein: usually they form rigid, uniform chains.

First author Horng Ou, a postdoctoral researcher in O'Shea's lab, describes E4-ORF3 as 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," says Ou.

New Techniques Reveal How E4-ORF3 Assembles "Ultrastructure" in the Cell Nucleus Working with researchers from the University of California, San Diego (UCSD), O'Shea's team used new techniques to show how E4-ORF3 assembles into a polymer "ultrastructure" in the nucleus.

This had not been possible with coventional electron microscopy. But thanks to the latest technology and skills of UCSD's team at its National Center for Microscopy and Imaging Research, led by co-author Mark Ellisman, the researchers could see the E4-ORF3 polymer bending, weaving and twisting its way through the nucleus:

"It does appear to have a single repeating pattern and creates a matrix that captures several different tumor suppressors and silences p53 target genes," says O'Shea.

At first the protein forms a dimer, comprising two subunits. In this form, it ignores its cellular targets. The team wondered perhaps it is only when it forms a polymer that E4-ORF3 starts binding aggressively to tumor suppressor targets.

So they tested this idea. They fused E4-ORF3 polymer mutants with lamin, a cellular protein that assembles intermediate filaments that make cells stable and strong.

Inside the nucleus, the fused proteins assembled into cylindrical superstructures that bind to and disrupt the function of PML, a tumor-suppressing protein complex. Implications: Tumor-Busting Viruses? The researchers hope their findings will help scientists create small drug molecules that destroy tumors in a way similar to the E4-ORF3 and lamin combination they tested: by binding to and disrupting large cellular components that allow cancer cells to proliferate unchecked.

Understanding more about the cell-hijacking mechanisms that viruses use could give further clues into how to develop treatments that undermine tumor cells. For example, it may be possible to engineer "tumor-busting" viruses as the basis of a self-perpetuating cancer therapy.

Such viruses would only be able to destroy cancer cells since they could only flourish inside cells where the p53 tumor suppressor was switched off. And when that cell is destroyed, the copies of the engineered virus would then seek out and kill the remaining cancer cells all over the body.

The researchers say to engineer such viruses you would first have to find a way to disable E4-ORF3's ability to inactivate p53 in healthy cells: otherwise the viruses would seek out healthy cells too. But you can't remove E4-ORF3 altogether, because it does have some useful functions: for example, it allows the virus to replicate in the first place.

These subtle points help to illustrate the importance of the detailed, painstaking efforts that will be required to understand all the nuances of viral protein structures, functions and interactions, before E4-ORF3, and similar proteins, can be used in cancer therapies.

Funds from the National Institutes of Health, American Cancer Society, Sontag Foundation, the Arnold and Mabel Beckman Foundation, and Anna Fuller Foundation helped pay for the research.

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