Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy

被引:51
作者
DeVine, Tiffany
Dai, Mu-Shui
机构
[1] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Sch Med, Portland, OR 97239 USA
[2] Oregon Hlth & Sci Univ, OHSU Knight Canc Inst, Portland, OR 97239 USA
关键词
p53; MDM2; MDMX; ubiquitination; proteasome; cell cycle; apoptosis; deubiquitinating enzyme; ubiquitin ligase; TUMOR-SUPPRESSOR P53; CELL-CYCLE ARREST; SMALL-MOLECULE INHIBITORS; STRUCTURE-BASED DESIGN; RIBOSOMAL-PROTEIN L11; LI-FRAUMENI-SYNDROME; DEUBIQUITINATING ENZYME USP2A; ATM-DEPENDENT PHOSPHORYLATION; AUTOREGULATORY FEEDBACK LOOP; MDM2 GENE AMPLIFICATION;
D O I
10.2174/1381612811319180009
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Within the past decade, there has been a revolution in the types of drugs developed to treat cancer. Therapies that selectively target cancer-specific aberrations, such as kinase inhibitors, have made a dramatic impact on a subset of patients. In spite of these successes, there is still a dearth of treatment options for the vast majority of patients. Therefore, there is a need to design therapies with broader efficacy. The p53 tumor suppressor pathway is one of the most frequently altered in human cancers. However, about half of all cancers retain wild-type p53, yet through various mechanisms, the p53 pathway is otherwise inactivated. Targeting this pathway for reactivation truly represents the "holy grail" in cancer treatment. Most commonly, destabilization of p53 by various components of ubiquitin-proteasome system, notably the ubiquitin ligase MDM2 and its partner MDMX as well as various deubiquitinating enzymes (DUBs), render p53 inert and unresponsive to stress signals. Reinstating its function in cancer has been a long sought-after goal. Towards this end, a great deal of work has been devoted to the development of compounds that either interfere with the p53-MDM2 and p53-MDMX interactions, inhibit MDM2 E3 activity, or target individual DUBs. Here we review the current progress that has been made in the field, with a special emphasis on both MDM2 and DUB inhibitors. Developing inhibitors targeting the upstream of the p53 ubiquitination pathway will likely also be a valuable option.
引用
收藏
页码:3248 / 3262
页数:15
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