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A decisive function...
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Buschke, SusanneDivision of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany
(author)
A decisive function of transforming growth factor-β/Smad signaling in tissue morphogenesis and differentiation of human HaCaT keratinocytes
- Article/chapterEnglish2011
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Numbers
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LIBRIS-ID:oai:DiVA.org:uu-149802
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-149802URI
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https://doi.org/10.1091/mbc.E10-11-0879DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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The mechanism by which transforming growth factor-β (TGFβ) regulates differentiation in human epidermal keratinocytes is still poorly understood. To assess the role of Smad signaling, we engineered human HaCaT keratinocytes either expressing small interfering RNA against Smads2, 3, and 4 or overexpressing Smad7 and verified impaired Smad signaling as decreased Smad phosphorylation, aberrant nuclear translocation, and altered target gene expression. Besides abrogation of TGFβ-dependent growth inhibition in conventional cultures, epidermal morphogenesis and differentiation in organotypic cultures were disturbed, resulting in altered tissue homeostasis with suprabasal proliferation and hyperplasia upon TGFβ treatment. Neutralizing antibodies against TGFβ, similar to blocking the actions of EGF-receptor or keratinocyte growth factor, caused significant growth reduction of Smad7-overexpressing cells, thereby demonstrating that epithelial hyperplasia was attributed to TGFβ-induced "dermis"-derived growth promoting factors. Furthermore impaired Smad signaling not only blocked the epidermal differentiation process or caused epidermal-to-mesenchymal transition but induced a switch to a complex alternative differentiation program, best characterized as mucous/intestinal-type epithelial differentiation. As the same alternative phenotype evolved from both modes of Smad-pathway interference, and reduction of Smad7-overexpression caused reversion to epidermal differentiation, our data suggest that functional TGFβ/Smad signaling, besides regulating epidermal tissue homeostasis, is not only essential for terminal epidermal differentiation but crucial in programming different epithelial differentiation routes.
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Stark, Hans-JürgenDivision of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany
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Cerezo, AnaCentro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
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Prätzel-Wunder, SilkeDivision of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany
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Boehnke, KarstenDivision of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany
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Kollar, JasminDivision of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany
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Langbein, LutzDivision of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany
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Heldin, Carl-HenrikUppsala universitet,Ludwiginstitutet för cancerforskning(Swepub:uu)carlheld
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Boukamp, PetraDivision of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany
(author)
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Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, GermanyCentro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
(creator_code:org_t)
Related titles
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In:Molecular Biology of the Cell22:6, s. 782-7941059-15241939-4586
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