Abstract
MDM family proteins are crucial regulators of the oncosuppressor p53. Alterations of their gene status, mainly amplification events, have been frequently observed in human tumors.MDM4 is one of the two members of the MDM family. The human gene is located on chromosome 1 at q32-33 and codes for a protein of 490aa. In analogy to MDM2, besides the full-length mRNA several transcript variants of MDM4 have been identified. Almost all variants thus far described derive from a splicing process, both through canonical and aberrant splicing events. Some of these variants are expressed in normal tissues, others have been observed only in tumor samples. The presence of these variants may be considered a fine tuning of the function of the full-length protein, especially in normal cells. In tumor cells, some variants show oncogenic properties.This review summarizes all the different MDM4 splicing forms thus far described and their role in the regulation of the wild type protein function in normal and tumor cells. In addition, a description of the full-length protein structure with all known interacting proteins thus far identified and a comparison of the MDM4 variant structure with that of full-length protein are presented. Finally, a parallel between MDM4 and MDM2 variants is discussed.
Highlights
The murine Mdm4 protein (transformed mouse 3T3 cell double minute 4), formerly named Mdmx, has been identified in 1996 as a p53 binding protein [1]
The murine Mdm4 protein, formerly named Mdmx, has been identified in 1996 as a p53 binding protein [1]
Various groups have shown the ability of MDM4 to potentiate E3 ubiquitin ligase activity of MDM2 and/or to restore function of inactive mutant MDM2 suggesting that MDM4 can contribute to the MDM2 E3 function [17,18,19,20,21]
Summary
The murine Mdm4 protein (transformed mouse 3T3 cell double minute 4), formerly named Mdmx, has been identified in 1996 as a p53 binding protein [1]. S289 is phosphorylated by Casein Kinase 1 (CK1) This modification strengthens the association between MDM4 and p53 and the inhibition of p53 transcriptional function by MDM4 [32]; Point mutation of MDM4 basic amino acid, K468, impairs MDM4 binding to importin and nuclear translocation after DNA damage suggesting a potential role for this association at least under some conditions.
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