News Release

New binding target for oncogenic viral protein

Peer-Reviewed Publication

American Society for Biochemistry and Molecular Biology

Bethesda, MD – The DNA tumor virus simian virus 40 produces the Large T antigen which inactivates two of the cell's most important cancer-preventing proteins, p53 and pRb. In a study published in the Journal of Biological Chemistry, researchers at the Fred Hutchinson Cancer Research Center report the discovery of an additional target for T antigen--a protein called Fbw7.

The Fbw7 gene is located in a chromosomal region that is deleted in up to 30% of human tumors. "Fbw7 is itself an important tumor suppressor which makes it an attractive choice for inactivation by Large T," explained Dr. Markus Welcker, the study's first author.

The research appears as the "Paper of the Week" in the March 4 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

DNA tumor viruses proliferate by hijacking their host cell's DNA replication machinery. In order to do this, they have evolved mechanisms to override normal cellular replication controls. Simian virus 40 (SV40) accomplishes this task by producing the highly oncogenic large T antigen. This protein corrupts the cellular checkpoint mechanisms that guard cell division and the transcription, replication and repair of DNA. T antigen also inactivates some of the most important proteins that protect cells against malignant transformation, including tumor suppressor proteins p53 and pRb.

In the Journal of Biological Chemistry paper, Dr. Welcker and Dr. Bruce Clurman report that T antigen also binds to another tumor suppressor, Fbw7. This protein is part of a ubiquitin ligase complex that adds ubiquitin to proteins to mark them for destruction by the cell. Fbw7 recognizes a destruction signal on certain proteins that need to be degraded and brings them in close proximity to the enzymes that attach ubiquitin. The proteins recognized by Fbw7 play key roles in cell division, cell growth, differentiation, and cell death.

"These proteins are also some of the most broadly acting cellular oncogenes, and include cyclin E, c-Myc, Notch, and c-Jun," noted Dr. Clurman. "When Fbw7 is mutated in cancers, deregulation of these oncogenic Fbw7 targets is thought to contribute to cancer. SV40 T antigen contains a motif that mimics the destruction signal found in these proteins." However, unlike the other substrates recognized by Fbw7, T antigen is not destroyed by the cell.

Drs. Clurman and Welcker suspect that by acting as a decoy and binding to Fbw7, T antigen protects cellular Fbw7 targets that facilitate viral replication and tumorigenesis.

"I think this work underlines the importance of Fbw7 as an emerging tumor suppressor and the consequences of its loss in tumors," Dr. Welcker emphasized.

"The study of DNA tumors viruses has been an extremely important tool in understanding the cellular pathways that regulate cell division and are disrupted in cancer. Understanding the mechanisms through which these viruses interact with the cellular machinery that regulates cell division may lead to new insights into the pathways that cause cancer. This is an important step to designing new cancer treatment strategies that target these pathways," concluded Dr. Clurman.

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The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at www.jbc.org.

The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.

Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through its publications, the Journal of Biological Chemistry, The Journal of Lipid Research, Molecular and Cellular Proteomics, and Biochemistry and Molecular Biology Education, and the holding of scientific meetings.

For more information about ASBMB, see the Society's website at www.asbmb.org.


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