| Suprabasal Dsg2 expression in transgenic mouse skin confers a hyperproliferative and apoptosis-resistant phenotype to keratinocytes. | |
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MedLine Citation:
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PMID: 17284515 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Donna Brennan; Ying Hu; Sohaila Joubeh; Yoo Won Choi; Diana Whitaker-Menezes; Thomas O'Brien; Jouni Uitto; Ulrich Rodeck; My G Mahoney |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-02-06 |
Journal Detail:
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Title: Journal of cell science Volume: 120 ISSN: 0021-9533 ISO Abbreviation: J. Cell. Sci. Publication Date: 2007 Mar |
Date Detail:
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Created Date: 2007-02-22 Completed Date: 2007-07-31 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 0052457 Medline TA: J Cell Sci Country: England |
Other Details:
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Languages: eng Pagination: 758-71 Citation Subset: IM |
Affiliation:
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Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / genetics, physiology* Cell Adhesion / genetics, physiology Cell Differentiation / genetics, physiology Cell Proliferation* Cell Survival / genetics, physiology Desmoglein 2 / genetics, metabolism*, physiology Epidermis / metabolism, pathology, ultrastructure Immunoblotting Immunohistochemistry Keratinocytes / cytology, metabolism* Keratosis / metabolism, pathology Mice Mice, Transgenic Microscopy, Electron, Transmission Phenotype Protein Precursors / genetics, metabolism Signal Transduction / genetics, physiology |
| Grant Support | |
ID/Acronym/Agency:
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AR47938/AR/NIAMS NIH HHS; CA81008/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Desmoglein 2; 0/Protein Precursors; 60108-77-2/involucrin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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