Functional MDM2 Ablation in HK1.ras/fos-Δ5PTEN Transgenic Mice Results in an Elevated, p53-Mediated Block of Carcinogenesis that Depends upon p53 Expression

Moula, S., Greenhalgh, D. and Turnbull, G. (2023) Functional MDM2 Ablation in HK1.ras/fos-Δ5PTEN Transgenic Mice Results in an Elevated, p53-Mediated Block of Carcinogenesis that Depends upon p53 Expression. British Journal of Dermatology 189(1):e16. Meeting Abstract: British Society for Investigative Dermatology (BSID) Annual Meeting, Technology & Innovation Centre, University of Strathclyde, Glasgow, Scotland, 20–21 March 2023. (doi: 10.1093/bjd/ljad174.028)

Abstract

MDM2 is a ubiquitin ligase that targets p53 for degradation and the efficacy of functional MDM2 knockout to protect p53 levels was shown to inhibit benign papilloma formation in HK1.ras transgenic mice. In skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of phosphatase and tensin homolog (PTEN)-mediated Akt regulation, p53 loss was a consistent theme leading to well-differentiated squamous cell carcinoma (SCC). Analysis of endogenous MDM2 status in HK1.ras/fos-Δ5PTENflx hyperplasia and papillomas showed that activated p-MDM2166 activity was initially confined to suprabasal layers with resultant elevated basal layer p53. However, with time, HK1.ras/fos-Δ5PTENflx papillomas exhibited reduced p53 levels in basal keratinocytes associated with increased p-MDM2166 activity, which coincided with malignant conversion, suggesting that suprabasal-to-basal increases in p-MDM2166 downregulated p53 giving a susceptibility to malignant conversion. Therefore, to assess whether removal of this MDM2 ability to degrade p53 could inhibit carcinogenesis in HK1.ras/fos-Δ5PTENflx mice, MDM2 exons 5 and 6, which bind p53 and chaperone for ubiquitination, were removed via a Cre/lox-P system driven by a keratin K14 promoter following treatment with topical RU486 (K14cre-Δ5/6MDM2flx/flx). RU486 treatment of HK1.ras/fos-Δ5PTENflx-Δ5/6MDM2flx/flx mouse skin resulted in a complete block of carcinogenesis in all animals for over 16 weeks due to elevated p53 expression. However, preneoplastic hyperplasia appeared to be relatively unaffected, despite excess p53 expression. In approximately 10–15% of animals, HK1.ras/fos-Δ5PTENflx-Δ5/6MDM2flx/flx mice developed overt tumours by 5–6 months. A similar finding was observed in HK1.fos-Δ5PTENflx keratoacanthoma (KA) aetiology, as here the early p53 expression in HK1.fos-Δ5PTENflx-Δ5/6MDM2flx/flx hyperplasia mediated by MDM2 loss also blocked KA aetiology. To assess whether this was specific to MDM2/p53 interactions, inducible p53 ablation was introduced into the HK1.fos-Δ5PTENflx KA model. This confirmed inhibition was specific to p53 expression, as all HK1.fos-Δ5PTENflx/p53 flx/flx tumours rapidly progressed to malignancy, regardless of MDM2 genetic status. Thus, MDM2 inhibition can limit carcinogenesis via maintaining p53 levels; however, this inhibition can be circumvented via p53 loss and, moreover, MDM2 inhibition would be counterproductive in SSC contexts that expressed gain-of-function p53 mutations.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David
• Authors: Moula, S., Greenhalgh, D., and Turnbull, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• ISSN: 0007-0963