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.