The additive effect of TGF-ß with TNF-α on type VII collagen gene expression to activate the expression of an extracellular matrix-related gene

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Susan De Curtis ¹, Stephen Aderaye ¹, Jonathan Bower ², Catharina Grulich ², Jennifer Hollox ², Sabin Scheetz ²

∗Correspondence author e-mail: Scheetzs @yahoo.com: ¹Oshawa Clinic, 17 King St E, Oshawa, ON L1H 1B9, Canada. ²University of Toronto - St. George Campus, Medical Sciences Building, Toronto, ON M5S 1A8, Canada

Abstract

Type VII collagen is the predominant, if not the exclusive, component of the anchoring fibrils, attachment structures stabilizing the association of the cutaneous basement membrane to the underlying dermis. In the skin, type VII collagen is synthesized by both dermal fibroblasts and epidermal keratinocytes. Alterations in the type VII collagen protein structure or lack of its expression due to mutations in the corresponding gene COL7A1 are the hallmark of dystrophic epidermolysis bullosa, a mechano-bullous skin disease characterized by extreme fragility of the skin and leading to development of sub-lamina densa blisters. In this study, we have examined whether the additive effect of TGF-ß with TNF-α on type VII collagen gene expression is exerted at the transcriptional level by activation of the corresponding a promoter. Specifically, we demonstrate that the TNF-α effect is mediated by NF-kB1/RelA (p50/p65) and RelA/RelA (p65/p65) NF-kB complexes binding the TNF-α response element (TaRE) located in the region [7252/7230], with RelA acting as the transcriptional activator. We provide definitive evidence for the role of both TGF-ß and TNF-α response elements as enhancer sequences, functioning in the context of a heterologous promoter in an additive manner in response to TGF-ß and TNF-α. This study provides the functional interaction between the two immediate-early transcription factors, SMAD and NF-kB, to activate the expression of an extracellular matrix-related gene, COL7A1.

Key words: Type VII collagen; TGF-Beta; SMAD; NF-kB; TNF-α

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