Abstract
MDM2 possesses three activities that, together, effectively inhibit the p53 tumor suppressor. First, it binds to p53 and sterically blocks p53 interaction with TATA box protein accessory factors thereby shutting down its transcriptional transactivation function. Second, MDM2 shuttles p53 from its site of action within the nucleus into the cytoplasm. Third, MDM2 is an E3 ligase that transfers ubiquitin onto lysine residues of p53. Ubiquitinated p53 is rapidly degraded by the 26S proteosome. Because the MDM2 oncoprotein mediates three progressive stages of inhibition, it is the principal regulator of p53 activity. TheMDM2gene is located on chromosome 12q14.3-q15 and is amplified in several types of neoplasms, most of which are of mesenchymal tissue origin. MDM2 binding to p53 can be inhibited by phosphorylation of either MDM2 or p53. The kinases responsible for this phosphorylation are activated by cell stressors in general (hypoxia, nitric oxide, hydrogen peroxide) and DNA damaging agents in particular (ionizing radiation, UV-light). MDM2 can be inhibited by RAS or MYC oncoproteins. RAS and MYC activate the tumor suppressor protein p19Arf which sequesters MDM2 into the nucleolus and, in doing so, allows p53 levels to rise. The MDM2gene is activated by p53, which means that, in effect, p53 inhibits itself through MDM2. The cell requires a fine balance of MDM2 and p53 to maintain cell growth and a rapid response to stressors. MDMX is a paralog of MDM2 that has retained the ability to inhibit p53 binding to TATA box protein accessory factors. MDMX does not possess other p53 inhibitory activities. There has been recent progress in the development of small molecules that block MDM2 from binding to p53. Although these molecules are in the early stages of development, it is hoped that they will contribute to the war on cancer. This chapter summarizes the key studies that have increased our understanding of the interplay between p53, MDM2, and MDMX.
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Momand, J., Aspuria, P.J., Furuta, S. (2005). MDM2 and MDMX Regulators of p53 Activity. In: Zambetti, G.P. (eds) The p53 Tumor Suppressor Pathway and Cancer. Protein Reviews, vol 2. Springer, Boston, MA. https://doi.org/10.1007/0-387-30127-5_7
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DOI: https://doi.org/10.1007/0-387-30127-5_7
Publisher Name: Springer, Boston, MA
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