RasHa activation interdicts compensatory p53/p21WAF expression in Fos/PTENnull skin carcinogenesis via initial p53 loss but retention of p21WAF limits malignant progression

Greenhalgh, D. , Yao, D., Quinn, J. and Macdonald, F. (2009) RasHa activation interdicts compensatory p53/p21WAF expression in Fos/PTENnull skin carcinogenesis via initial p53 loss but retention of p21WAF limits malignant progression. In: American Association for Cancer Research (AACR) 100th Annual Meeting, Denver, USA, 18-22 April 2009,

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To study multistage skin carcinogenesis, transgenic mice have been developed that express activated rasHa and fos oncogenes [HK1.ras, HK1.fos] and RU486-induced [cre/lox] ablation of PTEN [Δ5PTEN] exclusively in the epidermis. Previously, following HK1.ras/Δ5PTEN synergism in papillomatogenesis, malignant conversion was rare and required TPA promotion, which rapidly induced aggressive squamous cell carcinomas [SCCs]. As Fos is a major effecter of TPA activities, HK1.fos/Δ5PTEN co-operation exhibited a similar synergism, but here tumours progressed to benign, highly keratotic keratoacanthoma [KA], not carcinoma. This was due to high levels of p53 and p21 re-expression in papillomas, which accelerated keratinocyte differentiation resulting in the hallmark keratosis of KA. To determine whether compensatory p53/p21 expression would protect against additional rasHa activation, triple HK1.ras/fos/Δ5PTEN were established. Here rasHa activation interdicted KA etiology and mice now exhibited spontaneous SCCs. However, malignant 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 observed in TPA-treated HK1.ras/Δ5PTEN mice. In triple HK1.ras/fos/Δ5PTEN papillomatogenesis, p53 and p21 were expressed early, possibly to counter rasHa activation, but in the increasingly aggressive papilloma histotypes, p53 expression was reduced, as opposed to the increase observed in HK1.fos/Δ5PTEN KA aetiology. At this stage, p21 expression remained, but expression became reduced and finally lost in areas of overt SCC. Reduced p21 expression was concomitant with reduced keratin K1 and gain of K13 expression, both indicators of early malignancy. Thus, rasHa activation altered papillomatogenesis, producing a benign tumour context where compensatory [fos/PTEN-associated] p53/p21 expression no longer induced differentiation and resultant KA. However, p53/p21 expression did inhibit conversion, until first p53 became down regulated followed by p21, to give wdSCCs that would presumably progress to aggressive SCCs akin to p53/p21 negative, TPA-promoted SCCs. These data suggest that p53 loss elicits a susceptibility to conversion, an event initially protected by p21 that, until lost itself, limits the early stages of ras/fos/PTEN-mediated progression. Collectively, this model highlights mechanisms deployed to resist each stage of carcinogenesis, with a potential to identify the molecular determinants that interdict or enhance early conversion/progression. Thus, this approach may provide important implications for future therapies geared to reactivating p53/p21 functions and that target anti-ras/MAPK/fos or the AKT/mTOR signalling pathways.

Item Type:Conference Proceedings
Glasgow Author(s) Enlighten ID:Greenhalgh, Dr David and Yao, Dr Denggao and Quinn, Dr Jean
Authors: Greenhalgh, D., Yao, D., Quinn, J., and Macdonald, F.
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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