Compensatory p53/p21WAF-induced differentiation in Fos/PTENnull skin carcinogenesis is interdicted by RasHa activation but retention of p21WAF inhibits malignant progression

Macdonald, F., Yao, D., Quinn, J. and Greenhalgh, D. (2009) Compensatory p53/p21WAF-induced differentiation in Fos/PTENnull skin carcinogenesis is interdicted by RasHa activation but retention of p21WAF inhibits malignant progression. In: British Society for Investigative Dermatology (BSID) Annual Meeting, Royal Agricultural College, Cirencester, UK, 30 March - 1 April 2009,

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To study multistage skin carcinogenesis, transgenic mice have been developed that express activated rasHa or fos oncogenes [HK1.ras, HK1.fos] and RU486-induced [cre/lox] ablation of the PTEN tumour suppressor gene [Δ5PTEN] exclusively in the epidermis. Previously following HK1.ras/Δ5PTEN synergism in papillomatogenesis, TPA promotion was required to achieve malignant conversion, which rapidly induced aggressive squamous cell carcinomas [SCCs]. As fos is a major effector of TPA activities, HK1.fos/Δ5PTEN mice exhibited similar synergism in papillomatogenesis, but tumours progressed to keratoacanthoma [KA] not carcinoma due to expression of p53 and p21, which halted papilloma proliferation and accelerated differentiation to give the hallmark keratosis of KA. To determine whether compensatory p53/p21 would protect against additional rasHa activation, we report that KA did not arise in HK1.ras/fos/Δ5PTEN mice, instead tumours progressed to SCC. However conversion was delayed and incomplete, producing areas of well-differentiated SCC [wdSCC] within large, keratotic papillomas, rather than rapid progression to uniform, poorly/undifferentiated SCCs in TPA-treated [fos-activated] HK1.ras/Δ5PTEN mice. In HK1.ras/fos/Δ5PTEN papillomas, p53 and p21 were expressed early, possibly to counter rasHa activation, and in increasingly aggressive papilloma histotypes, basal layer p53 became reduced while at this stage, p21 expression was retained, until lost in overt areas of wdSCC. Thus, rasHa activation alters papillomatogenesis to produce a benign tumour context where compensatory, fos/PTEN-associated p53/p21 expression no longer induces differentiation into KA. However, p53/p21 expression inhibits conversion until p53 became down regulated, followed by p21, to give the wdSCCs that with time may progress to aggressive SCCs akin to the p53/p21 negative, TPA-promoted SCCs. This suggests p53 loss elicits a susceptibility to conversion, initially protected by p21 and in this context p21 limits early stages of malignant progression.

Item Type:Conference Proceedings
Additional Information:This was presented by specialist registrar Dr Fiona Macdonald and was awarded a Cormie Prize from GU Dermatolgy.
Glasgow Author(s) Enlighten ID:Greenhalgh, Dr David and Yao, Dr Denggao and Quinn, Dr Jean
Authors: Macdonald, F., Yao, D., Quinn, J., and Greenhalgh, D.
Subjects:R Medicine > RL Dermatology
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
519961Analysis of tumour progression via inducible PTEN, p53 or p21 knockoutDavid GreenhalghBritish Skin Foundation (BSF)S505MVLS MED - DERMATOLOGY
285634Analysis of adhesion receptor signalling deregulation in transgenic mouse skin cancer via inducible, keratinocyte-specific suppressor gene..David GreenhalghCancer Research UK (CAN-RES-UK)C1361/A2395MVLS MED - DERMATOLOGY