The p53 protein plays a central role in the mechanisms that defend the human body from cancer, including regulation of cell division and progression through the cell cycle, programmed death of cancerous cells (or “apoptosis”), and inducing the immune system to respond against cancer cells.
When DNA damage is detected in a cell (for example, following UV radiation), p53 activates genes that interrupt the cell cycle to ensure that damaged cells do not grow and propagate uncontrollably, leading to cancer. Functional p53 is therefore critical to human health, earning it the title of the “guardian of the genome.” When p53 itself is mutated or pathologically inhibited by its natural regulators, cells grow uncontrollably and may eventually form a cancerous tumor. Approximately half of all cancer patients at initial diagnosis have cancers that circumvent the p53 mechanism by deactivating mutations in p53 itself, commonly referred to as mutant p53. In the remaining cancer patients, the p53 mechanism is circumvented by activating or overexpressing the natural suppressor proteins of p53, including MDM2 and MDMX, making them an ideal target for novel cancer therapies.
MDM2 is the primary regulator of p53, which acts by shuttling p53 out of the nucleus and targeting it for degradation. MDMX, which generally acts to sequester p53, is most abundantly expressed in normal bone marrow cells. In the event of DNA damage, these two suppressor proteins detach from p53 so that it is activated to respond to DNA damage.
Low levels of p53 induce cell cycle arrest, which is the basis for the cell to repair DNA damage. High levels of p53 can, under certain circumstances, trigger apoptosis, a form of programmed cell death. This is one of the body’s natural defense mechanisms against cancer and for dealing with DNA damage. However, activation and overexpression of MDM2 and MDMX are found in a significant number of cancers that commonly present with Wild Type p53. In these cancers, cancer cells co-opt and over-activate some of the mechanisms used by normal cells to restrain p53 function, thereby nullifying the tumor suppression capabilities of Wild Type p53. In this environment, the cancer cell growth is left unchecked.