Abstract
Desmoglein 2 (Dsg2), a component of the desmosomal cell-cell adhesion structure, has been linked to invasion and metastasis in squamous cell carcinomas. However, it is unknown whether--and if so how--Dsg2 contributes to the malignant phenotype of keratinocytes. In this study, we addressed the consequences of Dsg2 overexpression under control of the involucrin promoter (Inv-Dsg2) in the epidermis of transgenic mice. These mice exhibited epidermal hyperkeratosis with slightly disrupted early and late differentiation markers, but intact epidermal barrier function. However, Inv-Dsg2 transgene expression was associated with extensive epidermal hyperplasia and increased keratinocyte proliferation in basal and suprabasal epidermal strata. Cultured Inv-Dsg2 keratinocytes showed enhanced cell survival in the anchorage-independent state that was critically dependent on EGF receptor activation and NF-kappaB activity. Consistent with the hyperproliferative and apoptosis-resistant phenotype of Inv-Dsg2 transgenic keratinocytes, we observed enhanced activation of multiple growth and survival pathways, including PI 3-kinase/AKT, MEK-MAPK, STAT3 and NF-kappaB, in the transgenic skin in situ. Finally, Inv-Dsg2 transgenic mice developed intraepidermal skin lesions resembling precancerous papillomas and were more susceptible to chemically induced carcinogenesis. In summary, overexpression of Dsg2 in epidermal keratinocytes deregulates multiple signaling pathways associated with increased growth rate, anchorage-independent cell survival, and the development of skin tumors in vivo.
Highlights
Desmosomes are intercellular junctions found primarily in epithelial tissues and in certain non-epithelial tissues including the meninges, dendritic reticular cells of lymph node follicles and myocardium (Cheng and Koch, 2004; Franke et al, 2006; McDonald et al, 2004)
Inv-Desmoglein 2 (Dsg2) transgenic mice developed normally with no gross abnormalities in skin or hair appearance compared to wildtype littermates
We assessed the expression of the Dsg2-Flag transgene in skin from adult (3 months old) transgenic mice by immunostaining with anti-Flag (Fig. 1B, left panels) and Dsg2specific MP6 antibodies (Fig. 1B, middle panels)
Summary
Desmosomes are intercellular junctions found primarily in epithelial tissues and in certain non-epithelial tissues including the meninges, dendritic reticular cells of lymph node follicles and myocardium (Cheng and Koch, 2004; Franke et al, 2006; McDonald et al, 2004). These adhesion structures are essential to maintaining tissue architecture during embryonic development and in the adult organism (Garrod et al, 2002). The hallmark feature of the desmosomes is the linkage of this transmembrane protein complex to keratin intermediate filaments forming a highly organized structure that allows cells and tissues to withstand mechanical stress and disruption (Cowin, 1994; Cowin and Burke, 1996; Green and Jones, 1996)
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