NEGATIVE REGULATORS OF TUMOR SUPPRESSOR p53 IN THE CONTEXT OF ANTICANCER THERAPY
O.Yu. Shuvalov,1 O.A. Fedorova, A.V. Petukhov,1,2 A.A. Daks,1 E.A. Vasilieva,1 T.A. Grigorieva,3 G.S. Ivanov,1 N.A. Barlev 1,*
1 Institute of Cytology RAS, St. Petersburg, 194064,
2 Institute of Hematology of Federal North-West Medical Research Centre, St. Petersburg, 197341,
and 3 St. Petersburg State Technological Institute, St. Petersburg, 190013;
* e-mail: nick.a.barlev@gmail.com
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.
Key words:
p53, E3-ubiquitin ligases, ubiquitin-dependent degradation, inhibitors of protein-protein interactions
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