The p53 Pathway:
Cancer, Fertility, Metabolic Control and the Central Nervous System
Arnold J. Levine
The p53 protein and the signal transduction pathway it controls respond to a wide variety of stress signals that can disrupt the fidelity of DNA replication and cell division. To prevent this, the p53 pathway initiates a process of cell cycle arrest, senescence, or apoptosis to either repair the errors or kill the cells containing the mutations. Central to this pathway are a series of proteins that respond to the stress signals and regulate the levels and activity of the p53 pathway. We have identified a number of single nucleotide polymorphisms (SNP) in the genes that regulate p53 activity and these SNPs can play a role in the incidence of cancers in a population, the age of onset of cancers and the response to therapy. Some haplotypes containing these SNPs appear to be under positive evolutionary selection pressure in some human populations as a result of the role of p53 in the implantation of embryos into the uterus and the impact of some SNPs on fecundity of mice and humans. These processes are mediated by the p53-regulated gene, Leukemia Inhibitory Factor, or LIF, a cytokine that is essential for the implantation of embryos. SNPs in the p53 gene, the MDM-4 gene and the LIF gene regulate the efficiency of implantation of embryos in humans; the p53 protein may also be involved in the surveillance of developmental abnormalities.
In addition, the p53 transcription factor regulates the synthesis of glutaminase-2, an enzyme that converts glutamine to glutamate in the mitochondria of both the liver and the brain. In the liver, glutamate is converted to alpha-keto-glutamate, which promotes oxidative phosphorylation. As glutaminase-2 is not synthesized in liver cancers, these cancers produce energy via aerobic glycolysis. Returning the glutaminase-2 gene to liver tumor cells increases glutamate levels and inhibits the growth of these cells. Thus, it appears that a metabolic regulator that restores oxidative phosphorylation can inhibit this type of cancer. In the brain, glutamate is a neurotransmitter and five different glutamate receptors are regulated by p53 in response to stress signals. Stress signals that activate p53 in the brain are communicated throughout the body by the glutamate receptors. Interestingly, three of the genes that can cause Parkinson’s Disease, as well as the Huntington gene, are regulated by p53 in the brain. The role of p53 in the central nervous system remains to be explored.