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 prote