Splicing Up Mdm2 for Cancer Proteome Diversity

Abstract

Cancer cells often have high expression of Mdm2. However, in many cancers mdm2 is alternatively spliced, with more than 40 mRNA variants identified. Many of the alternative spliced mdm2 mRNAs have the potential to encode truncated Mdm2 isoforms. These putative Mdm2 isoforms can theoretically increase the diversity of the cancer proteome. The 3 best characterized are Mdm2-A, Mdm2-B, and Mdm2-C. As described in this review, the exogenous expression of these isoforms results in paradoxical phenotypes of transformation-associated growth as well as the inhibition of growth. Interestingly, these Mdm2 isoforms contribute tumor-promoting capacity in p53-null backgrounds. Herein we describe how alternative splicing of mdm2 may result in Mdm2 protein products that alter signal transduction to promote tumorigenesis. The tumor promoting capacity of Mdm2 isoforms is discussed in the context of functions that do not require the inhibition of p53. When N-terminal portions of Mdm2 are missing, the biochemical functions encoded by exon 12 are proposed to become more important. This may result in growth promoting functions when wild-type p53 is absent or compromised. The p53-independent tumor promoting activity of Mdm2 is proposed to result from C-terminal biochemical contributions of DNA binding, RNA binding, nucleolar localization, and nucleotide binding.

PDIP38 is translocated to the spliceosomes/nuclear speckles in response to UV-induced DNA damage and is required for UV-induced alternative splicing of MDM2

“…It should be noted that the cellular functions of the truncated proteins remain an important area of investigation, since these are presumed to be expressed in many cancer cells. 29 Further studies are needed to determine the mechanisms of how PDIP38 participates in MDM2 alternative splicing in response to DNA damage, and whether this is specific to MDM2 or involves the splicing of other genes.…”

“…MDM2 alternatively spliced forms have been proposed to have roles outside of p53 regulatory functions 29 and can take on transforming capabilities that can promote unchecked cell division. 26,29,32,48 Our studies therefore point to a role of PDIP38 in the regulation of the alternative splicing of MDM2 in response to genotoxic stress. These splicing variants may transduce cellular processes and reflect adaptations that contribute to the maintenance of genomic stability.…”

“…26,[48][49][50] One example of a gene that is alternatively spliced in cancer cells is MDM2, which encodes the E3 ubiquitin ligase that regulates p53. 29,31,32 Alternative splicing of MDM2 transcripts is induced in cultured cells by UV and genotoxic stress. 26,49,51 The appearance of the splice variants has significance beyond their impact on p53 functions, since it has been shown that the truncated MDM2 proteins may exhibit growth-regulatory properties, 29 the ability to promote tumorigenesis in mice 52 and to transform cultured cells.…”

“…29,31,32 Alternative splicing of MDM2 transcripts is induced in cultured cells by UV and genotoxic stress. 26,49,51 The appearance of the splice variants has significance beyond their impact on p53 functions, since it has been shown that the truncated MDM2 proteins may exhibit growth-regulatory properties, 29 the ability to promote tumorigenesis in mice 52 and to transform cultured cells. 32 We therefore evaluated the potential participation of PDIP38 in alternative splicing of MDM2 in response to UV irradiation.…”

“…25 There are reports of numerous genes, including MDM2, that are alternatively spliced in response to genotoxic stress. 26 Dysregulation of alternative splicing of numerous genes, including MDM2, [29][30][31][32] have been associated with cancer. 27,28 The goal of this study was to understand the nuclear functions of PDIP38.…”