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Cancer related gene p53 not regulated as indicated by previous tissue culture research


Results may be relevant to drug development

The cellular cascade of molecular signals that instructs cells with fatally damaged DNA to self-destruct pivots on the p53 tumor suppressor gene. If p53 is inactivated, as it is in over half of all human cancers, checks and balances on cell growth fail to operate, and body cells start to accumulate mutations, which ultimately may lead to cancer. Not surprisingly, the regulation of this vital safeguard has been studied in great detail for many years but mainly in tissue culture, or in vitro, models.

A new mouse model, created by scientists at the Salk Institute for Biological Studies, suggests that what researchers have learned about the regulation of p53 activity from in vitro studies may not be relevant to living, breathing organisms. The Salk scientists’ findings are published in this week’s online early edition of the journal Proceedings of the National Academy of Sciences.

Until now, scientists had assumed, based on studies in cultured cells, that p53 had to be modified by attaching chemical groups to specific sites on the protein to function normally in the body. The new research indicates that these modifications are not necessary to activate p53 under conditions of stress or to prevent p53 from throwing a wrench into the cell cycle machinery, when nothing is wrong.

"The chemical modifications of the p53 protein that we thought were essential for its normal function may just fine-tune the activity of the protein under physiological conditions in a living organism, but they are not essential," explains lead investigator professor Geoffrey M. Wahl. "This new study focuses our attention on the network of regulators of p53 and how they are regulated."

"This study caused a big shift in how we think about p53," explains Salk scientist and first author Kurt Krummel. "You have to look at all interacting partners because after all, modifications of p53 itself might not be so important as modifications of negative regulators and co-activators."

Many chemotherapeutical drugs used to treat cancer exert their biological effects on tumor cells through activation of the p53 pathway. Having an accurate view of how p53 is regulated will allow the development of specific drugs that unleash the killing power of p53 by interfering with its negative regulators.

Our cells are vulnerable to DNA breaks caused by UV light, ionizing radiation, toxic chemicals or other environmental damages. Unless promptly and properly repaired, these DNA breaks can let cell division spiral out of control, ultimately causing cancer.

Under normal conditions, the p53 protein is very unstable and found only at very low levels in the cell. But when the cell senses that its DNA has been damaged, it slows down the degradation of p53, so that p53 protein levels can rise and initiate protective measures. When higher than normal levels of p53 tumor suppressor exist, there is enough p53 to bind to many regulatory sites in the cell’s genome to activate the production of other proteins that will halt cell division if the DNA damage can be repaired.

Or, if the damage is too severe for the breaks to be repaired, critical backup protection, also governed by the p53 tumor suppressor protein, kicks in. It initiates the process of programmed cell death, or apoptosis, which directs the cell to commit suicide, permanently removing the damaged DNA from the organism.

Since the p53 protein is able to trigger such drastic action as cellular suicide, the cells of the body must ensure that the p53 protein is only activated when damage is sensed and that the protein is quickly degraded when it is not needed. Until now, many scientists thought that specific modifications on the easily accessible tail end, or C-terminus, of the p53 protein are crucial for both, timely degradation or activation.

To explore the effects of these modifications in vivo, Salk scientists genetically engineered mice to produce a p53 protein with an altered C-terminus instead of the normal version. Previous tissue culture studies by several labs around the world indicated that tinkering with the tail end prevented the protein from being flagged for degradation or activation. Instead of accumulating in mouse cells and halting cell division in the genetically engineered mice, the altered p53 protein performed flawlessly: it was unstable when no DNA damage was present and was stable and fully functional when needed to halt the cycle cell to repair DNA damage or to induce apoptosis.

"It came as a complete surprise. We even used a system that would have allowed us to switch on the modified p53 protein at will because we feared that the mice might not be viable and would die during early embryonic development," says Krummel.

More detailed investigations revealed that the altered p53 protein still binds to Mdm2, one of the negative regulators of p53 that facilitate its degradation.

When p53 is activated by DNA damage the same sites that are modified when the protein is slated for degradation, a different kind of chemical modification, so-called acetylation, takes place. But without acetylation, p53 functions just as well in mice, found the researchers.

Cathy Yarbrough | EurekAlert!
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