Research Article MDM4 Isoform Expression in Melanoma Supports an Oncogenic Role for MDM4-A Abdullah Alatawi, 1 SoonJye Kho, 2 and Michael P. Markey 1 1 Department of Biochemistry and Molecular Biology, Wright State University, Dayton, OH 45435, USA 2 Department of Computer Science and Engineering, Wright State University, Dayton, OH 45435, USA Correspondence should be addressed to Michael P. Markey; michael.markey@wright.edu Received 30 August 2021; Revised 4 October 2021; Accepted 5 October 2021; Published 16 October 2021 Academic Editor: Nihal Ahmad Copyright © 2021 Abdullah Alatawi et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. e p53 tumor suppressor integrates upstream signals such as DNA damage and active oncogenes to initiate cell cycle arrest or apoptosis. is 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. ese changes in splicing must be considered in the design of therapeutic inhibitors of the MDM2/4 proteins for melanoma. 1. Introduction As it plays a critical role in the arrest of inappropriate cell growth, the p53 tumor suppressor gene (TP53) is mutated in approximately half of all human cancers [1]. In fact, it was mutational profiling of TP53 in squamous cell skin cancer that first implicated UV-induced dipyrimidine photoprod- ucts as oncogenic [2]. However, it has been reported that TP53 is mutated in only 6% of melanomas [3]. Lying at a critical junction between DNA damage sensing and arrest or cell death, it is essential for a cancer cell to therefore find another way to repress the activity of p53. Commonly, this is through expression of the primary inhibitors of p53: MDM2 and MDM4. Both are able to bind to p53 and prevent its ability to transactivate target genes [4–7], but only MDM2 acts as a ubiquitin ligase to target p53 for proteasomal destruction [8–10]. On the contrary, MDM4 overexpression is observed in many cancers [11], including melanomas. Ensembl contains at least 17 different transcripts derived from the MDM4 gene, five of which have level 1 evidence [12]. Interestingly, these transcripts result from alternative splicing which includes or excludes exons at different functional regions of the MDM4 gene. For example, the transcripts known as MDM4-211, MDM4-G, and MDM4- XALT2 all lack portions of the p53-binding domain while retaining the RING domain, through which MDM4 het- erodimerizes with MDM2 [13–15]. Conversely, MDM4-S and MDM4-XALT1 retain the p53-binding domain but lack the RING domain [14–16]. Clearly, the biological impact of MDM4 overexpression will depend on which transcripts are being expressed. Despite the importance of MDM4 in melanoma, however, there has never been a systematic study of which transcripts are present in human melanomas. 2. Materials and Methods Analysis of publicly available data: data were obtained from several public resources. Gene mutation fre- quency in melanoma was taken from the dataset SKCM-US, a 466-subject study of melanoma patients in the United States [17], and analyzed at the International Cancer Genome Consortium data portal [18]. e results published here are in whole or part based on data generated by the TCGA Research Network Hindawi Journal of Skin Cancer Volume 2021, Article ID 3087579, 7 pages https://doi.org/10.1155/2021/3087579