Abstract
Beta ig-h3 is an extracellular matrix protein whose expression is highly induced by transforming growth factor (TGF)-beta1. Whereas beta ig-h3 is known to mediate keratinocyte adhesion and migration, its effects on keratinocyte differentiation remain unclear. In the present study, it was demonstrated that expression of both beta ig-h3 and TGF-beta1 was enhanced during keratinocyte differentiation and that expression of the former was strongly induced by that of the latter. This study also asked whether changes in beta-h3 expression would affect keratinocyte differentiation. Indeed, down-regulation of beta ig-h3 by transfection with antisense beta ig-h3 cDNA constructs effectively inhibited keratinocyte differentiation by decreasing the promoter activities and thus expression of involucrin and transglutaminase. The result was an approximately 2-fold increase in mitotic capacity of the cells. Conversely, overexpression of beta ig-h3, either by transfection with beta ig-h3 expression plasmids or by exposure to recombinant beta ig-h3, enhanced keratinocyte differentiation by inhibiting cell proliferation and concomitantly increasing involucrin and transglutaminase expression. Recombinant beta ig-h3 also promoted keratinocyte adhesion through interaction with integrin alpha3beta1. Changes in beta ig-h3 expression did not affect intracellular calcium levels. Subsequent analysis revealed not only induction of Akt phosphorylation by recombinant beta ig-h3 but also blockage of Akt phosphorylation by LY294002, an inhibitor of phosphatidylinositol 3-kinase. Taken together, these findings indicate that enhanced beta ig-h3, induced by enhanced TGF-beta during keratinocyte differentiation, provoked cell differentiation by enhancing involucrin and transglutaminase expression through the integrin alpha3beta1 and phosphatidylinositol 3-kinase/Akt signaling pathway. Lastly, it was observed that beta ig-h3-mediated keratinocyte differentiation was caused by promotion of cell adhesion and not by calcium regulation.
Highlights
Transforming growth factor- (TGF-)1-inducible gene-h3 (ig-h3) was first cloned from A549 lung adenocarcinoma cells that had been stimulated with transforming growth factor (TGF)-1 [1, 2]. ig-h3 has since been shown to be an extracellular matrix protein that can be highly induced by TGF- in several cell types, including mammary epithelial cells, keratinocytes, and lung fibroblasts [1, 2]
Expression of ig-h3 and TGF-1 Is Enhanced during Keratinocyte Differentiation—Primary NHOKs were subcultured at every 70% confluence until they reached the post-mitotic stage of proliferation, at which time the culture was maintained for 12 days without further passage
The authors of the present study previously demonstrated that TGF-, a potent inducer of differentiation for normal epithelial cells known to localize in the normal epidermis [4], induces keratinocyte differentiation [19]
Summary
Transforming growth factor- (TGF-)1-inducible gene-h3 (ig-h3) was first cloned from A549 lung adenocarcinoma cells that had been stimulated with TGF-1 [1, 2]. ig-h3 has since been shown to be an extracellular matrix protein that can be highly induced by TGF- in several cell types, including mammary epithelial cells, keratinocytes, and lung fibroblasts [1, 2]. Down-regulation of ig-h3 by transfection with antisense ig-h3 cDNA constructs effectively inhibited keratinocyte differentiation by decreasing the promoter activities and expression of involucrin and transglutaminase.
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