Fos co-operation with PTEN loss elicits keratoacanthoma not carcinoma due to p53/p21^WAF-induced differentiation triggered by GSK3b inactivation and reduced AKT activity

Yao, D., Alexander, C.L., Quinn, J., Chan, W.-C., Wu, H. and Greenhalgh, D.A. (2008) Fos co-operation with PTEN loss elicits keratoacanthoma not carcinoma due to p53/p21^WAF-induced differentiation triggered by GSK3b inactivation and reduced AKT activity. Journal of Cell Science, 121(10), pp. 1758-1769. (doi: 10.1242/jcs.021147)

Abstract

To investigate gene synergism in multistage skin carcinogenesis, the RU486-inducible cre/lox system was employed to ablate PTEN function [K14.cre/D5PTENflx] in mouse epidermis expressing activated v-fos [HK1.fos]. RU486-treated HK1.fos/D5PTENflx mice exhibited hyperplasia, hyperkeratosis and tumours that progressed to highly differentiated keratoacanthomas rather than carcinomas, due to re-expression of high p53 and p21^WAF levels. Despite elevated MAP kinase activity, cyclin D1/E2 over expression and increased AKT activity forming areas of highly proliferative, papillomatous keratinocytes, increasing levels of GSK3b inactivation exceeded a threshold that induced p53/p21^WAF expression to halt proliferation and accelerate differentiation, giving the hallmark keratosis of keratoacanthomas. A pivotal facet to this GSK3b-triggered mechanism centred on increasing p53 expression in basal layer keratinocytes. This reduced activated AKT expression and released inhibition of p21^WAF, which accelerated keratinocyte differentiation, as indicated by unique basal layer expression of differentiation-specific keratin K1, alongside premature filaggrin and loricrin expression. Thus, fos synergism with PTEN loss elicited a benign tumour context where GSK3b-induced, p53/p21^WAF expression continually switched AKT-associated proliferation into one of differentiation, preventing further progression. This putative compensatory mechanism required the critical availability of normal p53 and/or p21^WAF otherwise deregulated fos, Akt and GSK3b associate with malignant progression.

• Item Type: Articles
• Additional Information: This study demonstrates direct co-operation between PTEN loss and activated fos in keratoacanthoma etiology and identifies sentinel mechanisms able to divert benign tumor keratinocytes into terminal differentiation programs, which bodes well for therapeutic development. This included high levels of GSK3b inactivation, previously associated with malignancy, which induced compensatory p53 and p21WAF expression at the benign tumour stage; whilst anti-apoptotic AKT activities inducing a differentiation response may have evolved from elimination of neoplastic cells that avoids apoptosis and compromise of epidermal barrier functions or tissue integrity. This novel p53/p21WAF mechanism linking PTEN/PI3K/AKT signaling, ras/MAPK/fos pathways and the GSK3b/b-catenin/WNT axis, highlights the value of inducible mouse models that yield insights into the importance of context and stage-specific, temporal gene expression to eventual tumour outcome.
• Keywords: Transgenic skin carcinogenesis, tumour progression, fos, PTEN, AKT, p53, p21, keratin K1, keratinocyte differentiation, benign tumour cell proliferation
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David
• Authors: Yao, D., Alexander, C.L., Quinn, J., Chan, W.-C., Wu, H., and Greenhalgh, D.A.
• Subjects: Q Science > QR Microbiology; R Medicine > RB Pathology; Q Science > QP Physiology
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities
• Research Group: Section of Dermatology
• Journal Name: Journal of Cell Science
• ISSN: 0021-9533
• Copyright Holders: Copyright © 2008 The Company of Biologists
• First Published: First published in Journal of Cell Science 121(10):1758-1769
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.