| Fifty years of cancer research has provided us with many clues on the development of cancer. We know the body has various natural defense mechanisms to prevent cancer, an extremely important one being the expression of the a tumor suppressor protein, p53. Approximately half of all tumors have lost p53 activity through mutation or deletion while the other half display a dysfunction in the p53 pathway. Functions of p53 are believed to include the activation of transcription of pro-apoptosic and cell cycle arrest genes causing apoptosis or G1 arrest once p53 is activated. p53-null mice develop spontaneous tumors between the ages of 3-6 months, and p53-null cells have a variety of abnormalities including defects in apoptosis, G1 arrest, and centrosome duplication. The cause of spontaneous tumorigenesis in p53-null mice is still unknown. To understand the complexity of p53 activation, a transgenic mouse strain, carrying a TP53 transgene backcrossed into the mouse p53-null background (named SWAP), was generated. Human p53 is up regulated after y-irradiation and UV-irradiation in SWAP cells and is phosphorylated normally by murine kinases responsible for activation of p53 after stress. However, human p53 did not protect against induced carcinogenesis after either genotoxic or oncogenic stress, comparable in phenotype to p53-null mice. Loss of human p53 activity after stress was found through immunoprecipitation and treatment with nutlin-3a to be due to an increase in Mdm2 binding. While dissociation of Mdm2 gave rise to partial human transgenic p53 activity, loss of Mdm4 by siRNA treatment, in addition to inhibition of Mdm2 binding, fully activated p53. Surprisingly, human p53 delays the mice from spontaneous tumorigenesis, possibly due to normal regulation of transrepression, G2 arrest, and/or centrosome duplication. This suggests a novel role for p53 in the prevention of spontaneous tumorigenesis that is distinct from its role in protection from genotoxic or oncogenic stress. Therefore, characterization of SWAP mice would lead to the understanding of how p53 inhibits spontaneous tumorigenesis under normal conditions. Consequently, the p53 function needed to prevent spontaneous tumorigenesis may be revealed. |
