14-3-3σ/Stratifin Expression in HK1.Ras/Fos-Δ5ptenflx Transgenic Mouse Skin Carcinogenesis Reveals an Early, Inhibitory Role; Lost During MDM2 Activated/P53 Inactivated Malignant Progression

McMenemy, C., Guo, D., Cochrane, A., Crookston, K., Boyle, J., Quinn, J. and Greenhalgh, D. A. (2017) 14-3-3σ/Stratifin Expression in HK1.Ras/Fos-Δ5ptenflx Transgenic Mouse Skin Carcinogenesis Reveals an Early, Inhibitory Role; Lost During MDM2 Activated/P53 Inactivated Malignant Progression. British Society for Investigative Dermatology (BSID) Annual Meeting, Manchester, UK, 3-5 April 2017.

McMenemy, C., Guo, D., Cochrane, A., Crookston, K., Boyle, J., Quinn, J. and Greenhalgh, D. A. (2017) 14-3-3σ/Stratifin Expression in HK1.Ras/Fos-Δ5ptenflx Transgenic Mouse Skin Carcinogenesis Reveals an Early, Inhibitory Role; Lost During MDM2 Activated/P53 Inactivated Malignant Progression. British Society for Investigative Dermatology (BSID) Annual Meeting, Manchester, UK, 3-5 April 2017.

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Abstract

The mechanisms driving or inhibiting skin carcinogenesis depend upon the contexts created by temporal acquisition of each mutation when pitted against the sentinel systems that have evolved to resist progression at each stage. To model this process, transgenic mice have been established that express activated rasHa and fos oncogenes together with RU486-inducible [K14.creP/lox-P] PTEN [5PTENflx] mutation exclusively in the epidermis. HK1.ras/fos/Δ5PTEN mice exhibit papillomas that convert to well-differentiated SCC following p53 loss and progress to SCCs following subsequent p21 loss/p-AKT1 activation. In addition, recently a suprabasal-to-basal increase in MDM2 activation [p-MDM2166] was observed associated with this p53 loss. Thus, given that 14-3-3σ/stratifin is a chaperone protein which removes/relocates MDM2 for degradation, 14-3-3σ/stratifin expression status in papillomatogenesis and progression to carcinoma was investigated. Already 14-3-3σ/Stratifin is known to play pivotal roles in keratinocyte growth, differentiation, and carcinogenesis but its exact protective [or potentially oncogenic] functions in differing tumour contexts remain unclear, as some studies show that 14-3-3σ/stratifin acts as a tumour suppressor and loss drives cancer; whilst others show increased expression associates with tumour invasion. Initially, compared to normal skin, RU486-treated tri-genic ras/fos/PTENflx epidermis expressed elevated 14-3-3σ/stratifin in resultant hyperplasia, and 14-3-3σ/stratifin remained strongly expressed in both basal and suprabasal layers of p53+ve /p21+ve papillomas. However, 14-3-3σ/stratifin expression diminished following malignant conversion, concomitant with p53 loss but persistent p21 expression. New HK1.ras/fos/5PTEN data demonstrate that this 14-3-3σ reduction/loss in basal layer keratinocytes was also associated with the suprabasal-to-basal expression of activated p-MDM2166; consistent with a mechanism of reduced basal layer p53 expression driving the susceptibility of late-stage papillomas to malignant conversion. Further, in 3D living skin assays, reduction/loss in 14-3-3σ expression was associated with an increased invasive potential. Collectively these data suggest that, in this context, 14-3-3σ plays important tumour suppressive roles in papillomas which inhibit MDM2 function and help maintain p53. However, diminished 14-3-3σ expression may facilitate MDM2-mediated loss of p53 which aids malignant conversion.

Item Type:Conference or Workshop Item
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Greenhalgh, Dr David and Quinn, Dr Jean and MCMENEMY, Carol
Authors: McMenemy, C., Guo, D., Cochrane, A., Crookston, K., Boyle, J., Quinn, J., and Greenhalgh, D. A.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
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