Tumorigenesis promotes Mdm4-S overexpression

Abstract

Disruption of the p53 tumor suppressor pathway is a primary cause of tumorigenesis. In addition to mutation of the p53 gene itself, overexpression of major negative regulators of p53, MDM2 and MDM4, also act as drivers for tumor development. Recent studies suggest that expression of splice variants of Mdm2 and Mdm4 may be similarly involved in tumor development. In particular, multiple studies show that expression of a splice variant of MDM4, MDM4-S correlates with tumor aggressiveness and can be used as a prognostic marker in different tumor types. However, in the absence of prospective studies, it is not clear whether expression of MDM4-S in itself is oncogenic or is simply an outcome of tumorigenesis. Here we have examined the role of Mdm4-S in tumor development in a transgenic mouse model. Our results suggest that splicing of Mdm4 does not promote tumor development and does not cooperate with other oncogenic insults to alter tumor latency or aggressiveness. We conclude that Mdm4-S overexpression is a consequence of splicing defects in tumor cells rather than a cause of tumor evolution.

The long and the short of it: the MDM4 tail so far

“…Independently, the Lozano lab demonstrated that elevated MDM4-S transcript levels in tumors arise from splicing defects, rather than being selected for inherent oncogenic capacity. Consistently, MDM4-S protein levels did not accumulate in their transgenic MDM4-S B-cell lymphoma mouse model (Pant et al, 2017). It must be noted that these findings have been generated in mice, and variation between the murine and human MDM4 homologes exists (Shvarts et al, 1996).…”

Mechanisms of TP53 Pathway Inactivation in Embryonic and Somatic Cells—Relevance for Understanding (Germ Cell) Tumorigenesis

“…Similar to MDM2 and P53, MDM4 also has an isoform frequently occurring in tumors, Mdm4-S, where exon 6 is excluded from the protein [245]. It has been demonstrated to be highly expressed in B-cell leukemia, for which it may potentially serve as a biomarker [257]. Although Mdm4-S is prone to nonsense-mediated decay, its degradation is obstructed in B-lymphocytes, which leads to elevated levels of this isoform [257,373].…”

“…It has been demonstrated to be highly expressed in B-cell leukemia, for which it may potentially serve as a biomarker [257]. Although Mdm4-S is prone to nonsense-mediated decay, its degradation is obstructed in B-lymphocytes, which leads to elevated levels of this isoform [257,373]. This has been suggested to be the result of increased c-myc expression, which is overexpressed through amplification in many tumors [373,374].…”

“…Finally, Pant and colleagues observed increased MDM4-S expression in B-cell leukemia patients, however, they suggested that this isoform was a consequence of splicing defects in tumor cells rather than being a contributor to tumorigenesis [257]. These investigators also supported the notion that MDM4-S has the potential to become a biomarker for this cancer.…”

Loss of digestive organ expansion factor (Diexf) reveals an essential role during murine embryonic development that is independent of p53

“…Diexf is an evolutionarily conserved gene from yeast to humans, and recent studies in zebrafish have suggested that the Diexf protein is a negative regulator of p53 [ 9 , 15 ]. In many different human cancers with wild type TP53 , other TP53 inhibitors such as MDM2 and MDM4 are frequently amplified or overexpressed [ 8 , 21 ]. To ascribe a role of DIEXF in human cancers, we exploited the data from cBioPortal and examined whether a similar inverse correlation between TP53 and DIEXF exists [ 22 , 23 ].…”