Background of p53
Originally identified in its mutant form, p53 is now known to be one of the most commonly mutated tumor suppressor proteins found in human cancers. In fact, 50% of all cancers appear to harbor a mutation in p53. In healthy cells, low levels of p53 are maintained by a negative feedback loop in which p53 promotes Mdm2 ex
A growing field of research centers around the cytoplasmic, non-transcriptional tumor suppressor functions of p53. Briefly, overex
Regulation of p53 and its effects
In order to have these effects, p53 must accumulate in the cell. Several kinases are capable of activating p53 via phosphorylation following DNA damage; such posttranslational modifications can protect p53 from degradation. An alternative path for p53 accumulation is through the induction of pl9 ARF which can inhibit p53's degradation by Mdm2. Thus cellular stress causes p53 to buildup within the cell and this serves as an alarm signal that can lead to apoptosis, growth arrest, and cellular senescence in order to prevent tumorigenesis.
p53's involvement in tumorigenesis could take one of three forms: (1) Complete loss of wild type p53 leading to loss of the cell's growth-inhibitory response to physiologic or genotoxic stress. (2) Dominant negative function of mutant p53 such that mutant p53 is capable of inactivating the tumor suppressive function of wild type p53 i.e. inhibiting the formation of tetrameric complexes in cells. (3) Mutant p53 gain of function such as altered regulation of gene ex
p53 is known as a tumor suppressor gene, which is a hub of cellular signaling networks that is activated by other classes of DNA damage. Thus, it plays a critical role in guarding against cancer development; the loss of p53 function contributes to the development of most human cancers. The p53 pathway is composed of genes and their products that are targeted to respond to stress signals. More than seven negative and three positive feedback loops in the p53 pathway have identified.
The main feedback loop in the p53 pathway consists of p53 and MDM2. It is a negative feedback loop that keeps the p53 protein at low levels in cells under normal conditions. In contrast, the free p53 protein concentration increases in the damaged cells. Also, the PTEN is known as a tumor suppressor protein, which regulates the cellular localization of MDM2. When restricted to the cytoplasm, MDM2 is degraded and this inhibition of MDM2 makes a p53 positive feedback loop. Another positive feedback loop includes ARF . There is two possible way to keep p53 stabilization. One is MDM2 feedback loop interacting with p53 and another mechanisms to stabilize p53 is by inhibition of MDM2 ubiquitin ligase activity through ARF.
Most vertebrates have homologs of each protein in the p53 pathway but at least a few vertebrates, such as common bottle nose dolphin and brandy’s bat do not include the ARF feedback loop. We apply a technique of analyzing the network dynamics based on grouping genes into discrete modules that allows us to understand the qualitative effect of the ARF feedback loop on the dynamics of the p53 network. This analysis suggests that the ARF component can have an affect on organismal fitness and that the transition from an ancestor missing the ARF loop to species containing the ARF loop may have been selected for because of its affect on whole organism fitness in response to the risk of cancer.