Abstract
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.
Anti-Cancer Agents in Medicinal Chemistry
Title:Escape, or Vanish: Control the Fate of p53 through MDM2-Mediated Ubiquitination
Volume: 16 Issue: 2
Author(s): Jinlian Wei, Yingrui Yang, Mengchen Lu, Lili Xu, Fang Liu, Zhenwei Yuan, Qichao Bao, Zhengyu Jiang, Xiaoli Xu, Xiaoke Guo, Xiaojin Zhang, Qidong You and Haopeng Sun
Affiliation:
Keywords: Antitumor strategy, degradation, E3 ligase activity, MDM2, p53, ubiquitination.
Abstract: 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.
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Wei Jinlian, Yang Yingrui, Lu Mengchen, Xu Lili, Liu Fang, Yuan Zhenwei, Bao Qichao, Jiang Zhengyu, Xu Xiaoli, Guo Xiaoke, Zhang Xiaojin, You Qidong and Sun Haopeng, Escape, or Vanish: Control the Fate of p53 through MDM2-Mediated Ubiquitination, Anti-Cancer Agents in Medicinal Chemistry 2016; 16 (2) . https://dx.doi.org/10.2174/1871520615666150907093358
DOI https://dx.doi.org/10.2174/1871520615666150907093358 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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