MDM4 (MDMX) and its Transcript Variants

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.

Keywords: MDM2.; MDM4; MDM4-211; MDM4-S; p53; transcript variants.

Fig. (1).

Scheme of MDM4 protein domains and of regions involved in protein-protein interaction. The interaction proteins validated by in vivo binding assays are shown. Bold characters represent validated serine phosphorylation sites. Italic characters represent lysine sumoylation sites.

Fig. (2).

(a) Scheme of MDM4 mRNA organization in exons (according to the GeneBank NM 002393) paralleled to the structure of the MDM4 protein regions. (b) Scheme of mRNA of MDM4 variants.