Tuesday, October 16, 2012

Teaching an Old Protein New Tricks

Summary: Adenovirus, the virus that causes the common cold, has "instructions" in its DNA to create a protein labeled "E4-ORF3" that disables a gene whose job is to make cells which have damaged DNA self-destruct. The protein allows adenovirus to infect cells and have them stay alive for long enough to create more of the virus and burst so that the virus can spread to other cells. This is an important discovery because cancer and some other diseases could be cured by modifying this protein to make it activate the gene which makes damaged cells destruct. Cancer happens when cells start to reproduce uncontrollably, and it's caused by damaged DNA. If the modified protein was delivered to cells, it could "shut down" tumors slowly.


Relevance: Related to proteins, which we learned about in Unit 2 and 3.


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 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... Read more at: http://medicalxpress.com/news/2012-10-cold-viruses-cancer-therapies.html#jCp
Credit: Salk Institute for Biological Studies
Author unknown

4 comments:

  1. How would they be able to modify the protein?

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    1. They wouldn't modify the protein directly. Scientists are able to piece together DNA from different viruses and organisms, so they would use DNA from adenovirus, and another organism that produces proteins that are similar to the protein they are looking to produce. That way, they would modify the DNA, which provides instructions for making the protein, rather than trying to modify each individual protein by itself.

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  2. have they tested this on anyone with cancer yet?

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    1. Actually, they're far from testing their findings. They have just found out how cold disables the cell's "defenses", and realized the protein that does the work could be modified to make cancerous cells kill themselves off. They haven't actually tried to create the protein, so it will be a while before they start testing it on humans.

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