Extracellular Matrix-dependent Activation of Syndecan-1 Expression in Keratinocyte Growth Factor-treated Keratinocytes

Abstract

Syndecan-1 is a major heparan sulfate proteoglycan of the epidermis. Its expression is strongly induced in migrating and proliferating keratinocytes during wound healing and, on the other hand, diminished or lost in invasive squamous cell carcinoma. We have recently found in the syndecan-1 gene an enhancer (fibroblast growth factor-inducible response element (FiRE)) that activates gene expression in wound edge keratinocytes (Jaakkola, P., Kontusaari, S., Kauppi, T., Mä ä ttä , A., and Jalkanen, M. (1998) FASEB J. 12, 959 -969). Now, we demonstrate that the activation of this enhancer by keratinocyte growth factor (KGF) is modulated by the components of the extracellular matrix (ECM). MCA-3D mouse immortal keratinocytes growing on fibrillar collagen failed to activate FiRE and subsequently to induce syndecan-1 in response to KGF. The same cells growing on fibronectin or laminin, however, increased FiREdependent reporter gene expression upon KGF treatment. The inhibition of the KGF induction by collagen appears to be specific for signaling to FiRE, as the increase in cell proliferation by KGF was not affected. The effect was selective to KGF, as EGF-induction was independent on ECM composition. Changes in the transcription factor binding were not involved in the differential activation of FiRE, as the levels and composition of the AP-1 complexes were unchanged. However, application of anisomycin, an activator of Jun amino-terminal kinase, resulted in a lower response in cells growing on collagen compared with fibronectin. These results indicate that the composition of ECM and availability of growth factors can play a role in the epidermal regulation of syndecan-1 expression and that FiRE is a novel target for gene regulation by the extracellular matrix.

Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases?

“…Of the heparan sulphate‐containing proteoglycans, the cell surface‐associated proteoglycans of the syndecan, glypican and CD44 families, and the dermal–epidermal junction, basement membrane‐associated proteoglycan, perlecan, are all present in the skin 75,94 . Following dermal injury, the expression patterns of syndecan‐1, CD44 and perlecan have been described previously, 92,94–96 with syndecan‐1 strongly induced in proliferating, but not migrating, keratinocytes adjacent to acute wound margins and to some extent in ingrowing capillaries 92,96 . Within the dermis and epidermis, the expression of such proteoglycans differs with respect to sulphation level; low sulphated heparan sulphate proteoglycans appear in the basement membrane from day 7 after wounding and the highly sulphated epitope after 2 months postwounding 92,95 .…”

Structure and Regulation of the Envoplakin Gene

“…The following antibodies (all from Santa Cruz) were used to supershift or prevent formation of protein DNA complexes: M-19 for gut-enriched Klf4, C-20 for upstream stimulatory factor-1, N-262 for c-Myc, (D-20)-G for Sp3, and 1C6 for Sp1. 0.1-2 g of the antibodies were incubated with the nuclear extracts 10 min before addition of the labeled probe as described (28,29).…”

“…to be crucial for syndecan-1 enhancer activity in a keratinocyte cell line (29,53), c-Myc, which is known to regulate epidermal differentiation (54), and any of the several Klf family members recognized by polyclonal antibody M-19 against Klf4 (SantaCruz). Future work is needed to determine the exact nature of the transcription factors interacting with the MutE ϩ Klf site in the envoplakin promoter.…”

Altered Distribution and Expression of Syndecan-1 and -4 as an Additional Hallmark in Psoriasis

“…This result is not the first one showing the regulation of syndecan-1 expression by ECM components. It was demonstrated before that syndecan-1 expression is activated in keratinocytes cultured of FN upon treatment with keratinocyte growth factor (KGF) through a mechanism involving the fibroblast growth factor-inducible response element (FiRE) [ 45 ]. In our experimental conditions, syndecan-4 expression was not affected suggesting that each syndecan may have distinct roles in the pathogenesis of the disease.…”