Poster abstracts
Poster number 13 submitted by Daniel Comiskey
Tumorigenic functions of splice variant MDM2-ALT1 in p53 wildtype and p53 null mouse models
Daniel Comiskey (Nationwide Childrens Hospital), Aishwarya Jacob (Nationwide Childrens Hospital), Brianne Sanford (Nationwide Childrens Hospital), Aixa Tapia-Santos (Nationwide Childrens Hospital), Dawn Chandler (Nationwide Childrens Hospital)
Abstract:
The oncogene MDM2 undergoes alternative splicing in response to genotoxic stress. Subsequently, p53 becomes upregulated and activates downstream targets involved in apoptosis and cell cycle arrest. Despite this tumor-protective activity, alternatively-spliced variants of MDM2 have been linked to cancer including soft tissue sarcomas, breast, colon, bladder, and ovarian cancers. MDM2-ALT1, which consists of only the two terminal coding exons 3 and 12, is the most frequently observed of these splice isoforms. Consequently, there is a lack of clear understanding as to how MDM2-ALT1 can be both tumor protective and contribute to tumorigenesis, and whether this phenomenon is p53-dependent. Therefore in order to establish a causative relationship between MDM2 splicing and tumorigenesis we have developed a mouse model of conditional MDM2-ALT1 expression using a single copy of the human MDM2-ALT1 cDNA. Using a B cell-specific Cre promoter, CD19-Cre, we have identified that MDM2-ALT1 expression leads to increased lymphomagenesis and disruption of splenic architecture in aged mice. Surprisingly, in an age-matched cohort of MDM2-ALT1 mice we observe a decrease in B cell markers, but not T cell markers by flow cytometry in MDM2-ALT1-positive mice. We also report a p53-independent role of MDM2-ALT1 in carcinogenesis. In a cohort of pan-MDM2-ALT1-expressing p53-deficient mice we observe a decrease in their median survival. Additionally, we observe a modulation in the tumor spectrum of MDM2-ALT1-expressing mice from mostly lymphomas in control mice to soft tissue sarcomas in experimental mice. Furthermore, we observe an increase of pMdm2 (S395) and phosphorylated p19Arf protein expression in tumors isolated from experimental mice as compared to lymphomas from control mice. These data suggest that after an initial latent tumor protective phase, persistent MDM2-ALT1 expression is able to manifest tumorigenesis at a later stage through the selective pressure of oncogenic signals mediated through dysregulation of the Arf-Mdm2-p53 axis. Overall our findings highlight the importance of MDM2 splice variants as critical modifiers of both p53-dependent and p53-independent tumorigenesis, underscoring the complexity of MDM2 post-transcriptional regulation in cancer.
Keywords: MDM2, p53