Abstract

Abstract The murine double minute 2 (MDM2) protein is an E3 ubiquitin ligase most notable for priming tumour-suppressor p53 for degradation. MDM2 contains two promoters - the constitutive P1 and the inducible P2. The p53-independent P1 promoter is responsible for basal levels of MDM2, whilst the p53-dependent P2 promoter is activated upon stress responses. Although the oncogenic functions of MDM2 are well understood, less is known about the individual roles of the promoters and their contribution to tumorigenesis and stress responses. To tease apart the roles of the promoters, we have used genetically engineered mouse (GEM) models null for the P1-promoter and mutated for the P2-promoter in the context of intestinal cancer, lymphoma and hepatocellular carcinoma (HCC). Here, we have shown that mice with heterozygous or homozygous loss of the P1-promoter in the APCMin/+ intestinal model have extended survival and reduced intestinal tumour burden in comparison to the P1- wild type (WT), APCMin/+ mice. Surprisingly, none of the P1-null APCMin/+ mice succumbed to intestinal tumours, but rather to thymic lymphomas. In the P1-null APCMin/+ lymphoma samples, we investigated the p53 functionality by examining the expression levels of p21, a p53 downstream target. Immunohistochemistry analysis clearly revealed that p53 is non-functional as p21 was not expressed, despite variations in p53 expression levels itself. This uncommon occurrence in the APCMin/+ model led us to investigate the role of the P1 and P2 promoters in the Eµ-Myc lymphoma model. Interestingly, in this model, heterozygous loss of the P1 promoter improves survival, while heterozygous loss of the P2 promoter accelerates lymphomagenesis. Our findings thus far indicate a differential role for the P1 and P2 MDM2 promoters in tumorigenesis. In addition to using GEM models, we are investigating the role of the MDM2 promoters in stress-induced HCC. These studies will allow for a better understanding of MDM2 functions, but also perhaps provide an alternative therapeutic strategy for cancers with aberrations in the p53-MDM2 signalling axis. Citation Format: Narisa Phinichkusolchit, Thomas Jamieson, Rachel Ridgway, Dimitris Athineos, Kerryanne Crawford, Nikolina Vlatkovic, Mark Boyd, Owen Sansom, Karen Blyth. MDM2 P1 and P2 promoters have different roles in tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1620.

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