MDM4 Isoform Expression in Melanoma Supports an Oncogenic Role for MDM4-A

The p53 tumor suppressor integrates upstream signals such as DNA damage and active oncogenes to initiate cell cycle arrest or apoptosis. This response is critical to halting inappropriate growth signals. As such, p53 activity is lost in cancer. In melanoma, however, the p53 gene is intact in a reported 94% of human cases. Rather than direct mutation, p53 is held inactive through interaction with inhibitory proteins. Here, we examine the expression of the two primary inhibitors of p53, MDM2 and MDM4, in genomic databases and biopsy specimens. We find that MDM4 is frequently overexpressed. Moreover, changes in splicing of MDM4 occur frequently and early in melanomagenesis. These changes in splicing must be considered in the design of therapeutic inhibitors of the MDM2/4 proteins for melanoma.

Automated summary

The activity of p53 is lost in cancer, including melanoma, where the intact p53 gene is kept inactive through interaction with inhibitory proteins rather than direct mutation. The inhibitors MDM2 and MDM4 are frequently overexpressed in melanoma, with splicing changes in MDM4 occurring frequently and early in melanomagenesis. These splicing changes should be taken into consideration when designing therapeutic inhibitors of MDM2/4 proteins for melanoma.