X-ray Crystallography Reveals Cell's Fight Against Cancer

By the precise use of x-ray crystallography to monitor motion in very large molecules, researchers have captured a first look at the life-or-death struggle of a cancer-causing protein--LTag--and a major tumor-suppressor--p53.

Each lethal LTag (large T antigen) by itself ties up a group of six p53 molecules, inhibiting their tumor-suppressant role, the researchers reported in their study, which was published in the September 1, 2006, issue of the journal Genes & Development. Undaunted, the p53 molecules fight back by preventing replication of the virus that produces LTag, known as an oncoprotein because of its role in cancer growth. The winner of the battle depends on which side is healthier and stronger.

"If you have a lot of functional p53, you can override large T antigens,” said lead researcher Dr. Xiaojiang Chen, professor in molecular and computational biology at the University of Southern California (USC; Los Angeles, CA, USA) College of Letters, Arts, and Sciences.

Sometimes called the "guardian of the genome,” an injured p53 can leave a cell nearly defenseless. "p53 is a very important tumor suppressor that's mutated in a vast majority of all cancers,” stated Dr. James Pipas, professor of biologic sciences at the University of Pittsburgh (PA, USA).

Dr. Pipas, after studying LTag for many years, was astounded at its varied biologic functions--including very efficient tumor promotion—and named it the most amazing molecule in the universe in one of his presentations. Dr. Pipas called Dr. Chen's new study "a very important piece of work” that demonstrates how a healthy cell's tumor defenses break down. "Understanding exactly how this works is going to be a critical step toward our understanding of tumor genesis,” he said.

This, in turn, may lead to new methods for devising tumor-fighting drugs, Dr. Pipas added. Dr. Chen's team was able to describe the interaction between LTag and p53 by crystallizing the complex of one LTag and six p53 molecules, totaling more than 50,000 atoms between them. "It's quite a technical achievement, because these are fairly large proteins,” Dr. Pipas said.

Dr. Chen reported that his study gave him new respect for LTag and its parent, simian virus 40 (SV40). SV40 has long been used as a research tool to induce cancers in cell cultures. "Somehow this virus knows how important p53 is, and has this oncoprotein [Ltag] to target it by physically interacting with it and changing its conformation,” Dr. Chen said. If the virus succeeds, the outcome is a new tumor.



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