Monday, August 6, 2012

The relationship between p53 and Mdm2

The p53 and Mdm2 relationship is one of the most researched areas of signaling and has taught scientists many important signaling concepts. p53 is a specific transcription factor that functions as a tumor suppressor and causes damage to DNA. When there is no stress or DNA damage, p53 activity is not activated. When stress affects the body in some way, the p53 protein is activated due to phosphorylation. Depending on the stress or DNA damage, the p53 protein can activate a variety of genes that have the potential to cause inhibition of cell growth, DNA repair, apoptosis, or changes in cell differentiation.

(Image from: P53 Tumour Suppression)

The phosphorylation of p53 is quite complex and varies in the progression of the cell cycle of normal growing cells. This complexity affects its ability to associate with its regulatory proteins, such as Mdm2. The variety of p53 phosphorylation can be seen when one analyzes signaling in tumors. p53 phosphorylation is different in tumors and an increase in the degree of phosphorylation can be seen, as compared to normal cells and tissues. This increase in p53 phosphorylation indicates a failure of the p53 phosphatases to stop signaling.

Additionally, approximately 50% of all tumor types carry a p53 mutation. These mutations are typically seen in the DNA binding domain, which affects transcriptional activity and its overall cellular activities. The elevated expression of p53 leads to greater stability, which also induces the regulatory protein Mdm2. Mdm2 is a proto-oncogene that is amplified in approximately 7% of cancers and is frequently seen in soft tissue tumors. A proto-oncogene is a gene that becomes an oncogene, a gene that has the potential to cause cancer, through mutations or an increase in expression. The combination of a p53 mutation with overexpression of Mdm2 results in a worse prognosis for a patient, as compared to a patient with only the mutation or the overexpression.

Mdm2 protein has the activity of an ubiquitin ligase, which allows for the targeted degradation of its substrates, including p53. In addition to marking p53 for degradation, Mdm2 also binds to p53 and transports it out of the nucleus into the cytoplasm for degradation. The phosphorylation of p53 affects Mdm2’s ability to target p53 for degradation. When stress or DNA damage occurs in the body and the phosphorylation of p53 occurs on multiple sites, Mdm2 does not associate with p53. Researchers have recently discovered Mdm2 in human tumors and these scientists hypothesize that Mdm2 plays a role in tumorigenesis, with or without p53.

The relationship between p53 and Mdm2 has been shown to be vital to the normal functioning of the human cell, and also has other implications in cancer. Additionally, scientists have found that this relationship is an important part of a number of complex cellular signaling cascade pathways, including Ras, β-catenin, myc, Rb, and many more. The complexity of the p53-Mdm2 link illustrates the importance of this signaling pathway and indicates it is a viable therapeutic target. Researchers are studying this signaling relationship in order to design targeted drugs and therapies for cancer, as well as many other diseases.

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