MDM4 alternative splicing and implication in MDM4 targeted cancer therapies

The oncogenic MDM4, initially named MDMX, has been identified as a p53-interacting protein and a key upstream negative regulator of the tumor suppressor p53. Accumulating evidence indicates that MDM4 plays critical roles in the initiation and progression of multiple human cancers. MDM4 is frequently amplified and upregulated in human cancers, contributing to overgrowth and apoptosis inhibition by blocking the expression of downstream target genes of p53 pathway. Disruptors for MDM4-p53 interaction have been shown to restore the anti-tumor activity of p53 in cancer cells. MDM4 possesses multiple splicing isoforms whose expressions are driven by the presence of oncogenes in cancer cells. Some of the MDM4 splicing isoforms lack p53 binding domain and may exhibit p53-independent oncogenic functions. These features render MDM4 to be an attractive therapeutic target for cancer therapy. In the present review, we primarily focus on the detailed molecular structure of MDM4 splicing isoforms, candidate regulators for initiating MDM4 splicing, deregulation of MDM4 isoforms in cancer and potential therapy strategies by targeting splicing isoforms of MDM4.