p53 protein is a prominent tumor suppressor to induce cell cycle arrest, apoptosis
and senescence, which attracts significant interest to cancer treatment. Therefore, it would be
particularly important to restore the wild–type p53 that retains latent functions in the
approximately 50% of tumors. MDM2 (murine double minute 2), the principal cellular
antagonist of p53, has long been believed to suppress p53 activity through two main mechanisms: promoting degradation via its E3 ligase
activity and masking p53 transcriptional activation by direct binding. Targeting MDM2 E3 ligase activity is becoming a potential
antitumor strategy resulting from MDM2’s decisive role in controlling the fate of p53: p53 is going to degradation when entrapped into
MDM2-mediated ubiquitination, where p53 can escape by abrogating MDM2 E3 ligase activity using regulators. The intensive focus on
regulating MDM2 ubiquitin E3 ligase activity has led to the rapid progress of its inhibitors, which may be possible to help p53 escape
from degradation and restore its function to control tumor growth. This review summarizes the current inhibitors of MDM2 E3 ligase in
cancer therapy based on the understanding the regulation of MDM2 E3 ubiquitin ligase activity, including post-translational
modification, interactions between MDM2 and its cofactors, and regulation of MDM2 stability.
Keywords: Antitumor strategy, degradation, E3 ligase activity, MDM2, p53, ubiquitination.
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