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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
[NEGATIVE REGULATORS OF TUMOR SUPPRESSOR P53 IN THE CONTEXT OF ANTICANCER THERAPY]
Abstract:
P53 protein is considered to be the major tumor suppressor in human cells. Cancer cells do not survive if the p53-mediated signaling pathways function properly. However, about half of all malignancies still express wild type p53. One of the explanations to this is that p53 is suppressed by overexpression of p53-specific E3-ubiquitin ligases: Mdm2, MdmX, Pirh2 and Cop1. Pharmacological inhibition of protein-protein interactions between p53 and these negative regulators is a promising therapeutic approach to treat cancers retaining wild type p53. To date, a series of chemical inhibitors of p53 interactions with Mdm2 and MdmX E3-ubiquitin ligases have been discovered and characterized. Several of them are in the early stages of clinical trials. Despite this fact, their clinical efficacy may be hampered by a number of reasons, including tumor-specific expression of multiple isoforms of the target E3-ligases, which become inert to treatment with small molecules. This and other biochemical mechanisms of possible resistance of tumor cells with wild type p53 to small molecules against its negative regulators will be discussed in this review.
Insights
Wild-type p53 protein suppresses tumors, but cancer cells can evade this by overexpressing E3-ubiquitin ligases. Inhibiting these ligases is a promising cancer therapy, though resistance mechanisms exist.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The p53 protein is a critical tumor suppressor in human cells.
- Dysfunctional p53 signaling is implicated in numerous cancers.
- Wild-type p53 is expressed in about half of all malignancies, suggesting mechanisms of evasion.
Purpose of the Study:
- To review the therapeutic potential of inhibiting p53-E3-ubiquitin ligase interactions.
- To discuss resistance mechanisms against small molecule inhibitors targeting p53 negative regulators.
- To explore challenges in treating cancers with wild-type p53.
Main Methods:
- Literature review of studies on p53, E3-ubiquitin ligases (Mdm2, MdmX, Pirh2, Cop1), and small molecule inhibitors.
- Analysis of biochemical mechanisms of resistance in cancer cells.
- Discussion of clinical trial data for p53-Mdm2/MdmX inhibitors.
Main Results:
- Several small molecule inhibitors targeting p53 interactions with Mdm2 and MdmX have been developed.
- Some inhibitors are in early-stage clinical trials for cancer treatment.
- Tumor-specific expression of E3-ligase isoforms and other biochemical factors can lead to resistance.
Conclusions:
- Inhibiting p53-E3-ubiquitin ligase interactions is a viable therapeutic strategy for cancers with wild-type p53.
- Understanding and overcoming resistance mechanisms is crucial for clinical efficacy.
- Further research is needed to address challenges posed by isoforms and resistance pathways.
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