title: Suprabasal Dsg2 expression in transgenic mouse skin confers a hyperproliferative and apoptosis-resistant phenotype to keratinocytes.
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.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Brennan
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Sohaila
authors.initials: S
authors.lastname: Joubeh
authors.forename: Yoo Won
authors.initials: YW
authors.lastname: Choi
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rodeck
authors.forename: My G
authors.initials: MG
authors.lastname: Mahoney
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D051301:Desmoglein 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015151:Immunoblotting; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D007642:Keratosis / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D051301:Desmoglein 2; D011498:Protein Precursors; C032253:involucrin