Paradoxical maintenance of E-cadherin following inducible PTEN ablation in Ras or Fos-mediated skin carcinogenesis identifies sentinel mechanisms geared to combat PTEN dysfunction. (original) (raw)

Shaw, M., Yao, D., Quinn, J.A. and Greenhalgh, D.A. ORCID: https://orcid.org/0000-0002-6737-2744(2006) Paradoxical maintenance of E-cadherin following inducible PTEN ablation in Ras or Fos-mediated skin carcinogenesis identifies sentinel mechanisms geared to combat PTEN dysfunction. In: British Society for Investigative Dermatology Annual Meeting, Manchester, 10-12 April 2006, p. 247. (doi: 10.1111/j.1365-2133.2006.07327.x)

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Publisher's URL: http://dx.doi.org/10.1111/j.1365-2133.2006.07327.x

Abstract

E-cadherin, a cell adhesion protein that provides the spatial awareness for regulation of proliferation, differentiation and cell polarity is often lost or mutated in carcinogenesis. E-cad signalling failure to APC/Wnt/Lef1 pathways via β-catenin and ras-MAPK via α-catenin, occurs at the level of cell contact or in downstream effectors, such as the PTEN TSG, which acts as a scaffolding protein to co-ordinate E–cad signalling, and negatively regulates anti-apoptotic AKT expression, MAPK signalling and cell cycle. Given this E-cad/PTEN interaction, E-cad expression was investigated in multistage skin carcinogenesis mediated by epidermal ras^Ha or fos activation and RU486-inducible PTEN knockout [Δ5PTEN]. Here PTEN loss co-operated with ras^Ha and rapidly elicited papillomas but malignant conversion was rare, requiring TPA promotion. PTEN synergism with fos gave hyperkeratotic phenotypes expressing atypical differentiation markers and keratoacanthoma-like tumours [KAs] but no carcinomas. Western and immunefluorescence analysis showed that instead of the loss typically observed in carcinomas, all Δ5PTEN/ras^Ha carcinomas maintained E-cad expression, which became significantly elevated in Δ5PTEN/fos KAs. Thus, in being downstream of E-cad adhesion signalling, PTEN loss may be compensated for by increased or maintained E-cad expression due to a perceived potential threat to barrier maintenance. Such epidermal defence mechanisms possibly evolved to cope with carcinogenic insults yet avoid induction of apoptosis, a default mechanism available to internal epithelia, which would lead to barrier dysfunction. Indeed, the elevation observed in PTEN/fos KAs may echo this sentinel mechanism geared to divert keratinocytes with increased malignant/metastatic potential into differentiation pathways forming benign KA-like tumours and may explain in part why PTEN/ras^Ha papillomas required TPA promotion to achieve malignancy.

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