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New binding target for oncogenic viral protein

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
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Source:American Society for Biochemistry and Molecular Biology


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