Abstract
To investigate gene synergism in multistage skin carcinogenesis, the RU486-inducible cre/lox system was employed to ablate Pten function (K14.cre/Delta5Pten flx) in mouse epidermis expressing activated Fos (HK1.Fos). RU486-treated HK1.Fos/Delta5Pten flx mice exhibited hyperplasia, hyperkeratosis and tumours that progressed to highly differentiated keratoacanthomas, rather than to carcinomas, owing to re-expression of high p53 and p21 WAF levels. Despite elevated MAP kinase activity, cyclin D1 and cyclin E2 overexpression, and increased AKT activity that produced areas of highly proliferative papillomatous keratinocytes, increasing levels of GSK3beta inactivation induced a novel p53/p21 WAF expression profile, which subsequently halted proliferation and accelerated differentiation to give the hallmark keratosis of keratoacanthomas. A pivotal facet to this GSK3beta-triggered mechanism centred on increasing p53 expression in basal layer keratinocytes. This increase in expression 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 GSK3beta-induced p53/p21 WAF expression continually switched AKT-associated proliferation into differentiation, preventing further progression. This putative compensatory mechanism required the critical availability of normal p53 and/or p21 WAF, otherwise deregulated Fos, Akt and Gsk3beta associate with malignant progression.
Highlights
PTEN is a tumour-suppresser gene that has attracted significant interest given its high mutation frequency in human cancers and its roles in apoptosis/proliferation via negative regulation of AKT/PKB activity (Downward, 2004; Parsons, 2004)
Consistent with the direct protein-protein interactions that regulate p53 function (Freeman et al, 2003; Lei et al, 2006), Pten mutation in individuals with Cowden Disease results in cancer predisposition (Liaw et al, 1997) associated with cutaneous hyperkeratosis (Fistarol et al, 2002), suggesting that roles in keratinocyte differentiation can be added to PTEN activities that are essential for normal development
Given that the oncogene Fos is a major effecter of TPA promotion (Schlingemann et al, 2003) and cooperates with c-rasHa during papillomatogenesis and malignant conversion (Greenhalgh et al, 1990; Greenhalgh et al, 1993a; Greenhalgh et al, 1995; Saez et al, 1995), this study investigated whether activated Fos would cooperate with PTEN loss in papillomatogenesis and drive this crasHa-independent Δ5Pten-mediated mechanism of malignant progression
Summary
PTEN is a tumour-suppresser gene that has attracted significant interest given its high mutation frequency in human cancers and its roles in apoptosis/proliferation via negative regulation of AKT/PKB activity (Downward, 2004; Parsons, 2004). In classic two-stage DMBA/TPA chemical carcinogenesis, AKT activation and GSK3β inactivation typically correlate with tumour progression (Leis et al, 2002; Segrelles et al, 2006). Employing conditional PTEN knockouts, studies showed that DMBA-initiated c-rasHa (Hras1) activation achieved increased malignancy after TPA promotion (Suzuki et al, 2003). Two-stage chemical carcinogenesis using heterozygous Pten knockouts identified a mutual exclusivity between Pten loss and c-rasHa activation (Mao et al, 2004). This was partly resolved on finding that synergism of c-rasHa with Pten loss (Li et al, 2002)
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