Activated p-AKT, but not MDM2, drives malignant progression in Ras/Fos/PTEN^null skin carcinogenesis via p53/p21 loss and elevated cyclin D1/E2 expression (original) (raw)

Macdonald, F.H., Yao, D., Quinn, J.A. ORCID: https://orcid.org/0000-0002-8267-0993 and Greenhalgh, D.A. ORCID: https://orcid.org/0000-0002-6737-2744(2013) Activated p-AKT, but not MDM2, drives malignant progression in Ras/Fos/PTENnull skin carcinogenesis via p53/p21 loss and elevated cyclin D1/E2 expression.Journal of Investigative Dermatology, 133(S1), S57-S57. (doi: 10.1038/jid.2013.96)

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Abstract

Tumour progression depends on a complex combination of the genetic mutation milieu pitted against the sentinel systems that have evolved to resist carcinogenesis at each specific stage. To investigate tumour progression mechanism in transgenic mouse skin carcinogenesis, inducible PTEN ablation [Δ5PTEN] was introduced into the epidermis of mice expressing activated ras^Ha/fos oncogenes. RU486-treated HK1.ras/fos-Δ5PTEN mice exhibited accelerated papillomatogenesis but malignant conversion was delayed due to compensatory p53/p21 expression. Following p53 loss malignant progression was limited to well-differentiated squamous cell carcinoma via persistent p21 expression and down regulation of cyclin E2. Analysis of AKT activity during papillomatogenesis showed reduced p-AKT expression, associated with fos/PTEN feedback, which returned following p53 loss to circumvent/antagonise p21 expression; co-operate with MAPK signalling [i.e. elevated ERK1/2 expression]; and accelerate tumour progression via increased cyclin D1 and E2 expression. In contrast elevated, suprabasal MDM2 expression in p53-positive papillomas was lost in parallel to p53 loss; hence sustained MDM2-mediated p53 ubiquination does not appear to influence this progression mechanism. These data suggest p53/p21 counter deregulated MAPK signalling during papillomatogenesis and help minimise consequences of PTEN loss via p-AKT inhibition. Stepwise p53/p21 loss subsequently facilitates ras/MAPK/fos co-operation with PTEN/AKT activities to accelerate malignant progression via major failures in cell cycle control. The interplay between these common mutations thus create unique contexts that have important implications for therapies geared to reactivating p53/p21 functions or that target ras/MAPK/fos and PTEN/AKT signalling pathways.

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Funder and Project Information

1

Analysis of tumour progression via inducible PTEN, p53 or p21 knockout.

David Greenhalgh

3013

MVLS MED - DERMATOLOGY

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