THE INTERPLAY BETWEEN THE TUMOUR SUPPRESSOR P53 AND ITS NEGATIVE REGULATORS MDM2 AND MDMX
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p53 is a crucial tumour suppressor that is dysfunctional in most types of cancer. The TP53 gene is frequently mutated in many cancers, resulting in loss of p53 expression or production of mutant p53 proteins that are unable to inhibit tumour development. In cancer where wild-type p53 is expressed, tumour cells develop mechanisms to prevent activation of p53. Inactivation of p53 is commonly achieved through upregulation of the negative regulators MDM2 and MDMX, which directly inhibit p53 activity and promote p53 degradation. Restoration of p53 tumour-suppressive function can effectively inhibit tumour progression and stimulate tumour regression, which provides an attractive target for cancer therapy. Prior studies have detailed the mechanism of MDM2- and MDMX-mediated p53 inhibition by focusing on the inhibitory complex formed between the p53-binding domain of MDM2 or MDMX and the p53 transactivation domain. However, emerging evidence suggests that the acidic domains of MDM2 and MDMX play key roles in regulating p53 ubiquitination and DNA interaction. In this study, I further characterized the interaction between acidic domain of MDM2 and the DNA-binding domain of p53 using calorimetric techniques and NMR spectroscopy. Adding new context to this intermolecular interaction, I demonstrated that the acidic domain of MDM2 can directly bind to the p53 C-terminal regulatory domain. I also evaluated the role of the p53 transactivation domain in regulating the interaction between the acidic domain of MDM2 and the p53 DNA binding domain. Importantly, I have newly demonstrated that the acidic domain of MDMX is a direct intermolecular binding partner for the MDM2 p53-binding domain. Through these findings, I have proposed a new working model for the interplay between the tumour suppressor p53 and its negative regulators MDM2 and MDMX while highlighting some important questions that need to be addressed in future studies.