Cooperation between SMAD and NF-κB in growth factor regulated type VII collagen gene expression

Abstract

We have previously demonstrated that transforming growth factor-b (TGF-b) and pro-in¯ammatory cytokines, such as tumor necrosis factor-a (TNF-a) or interleukin-1b, synergistically enhance the expression of type VII collagen gene (COL7A1) in human dermal ®broblasts in culture (Mauviel et al., 1994). Recently, we identi®ed a SMAD-containing complex, rapidly induced by TGF-b and binding the region [7496/7444] of the COL7A1 promoter, responsible for COL7A1 gene transactivation (Vindevoghel et al., 1998a). In this report, we demonstrate that TGF-b and TNF-a response elements are distinct entities within the COL7A1 promoter. In particular, we demonstrate that the TNFa e ect is mediated by NF-kB1/RelA (p50/p65) and RelA/RelA (p65/p65) NF-kB complexes binding the TNF-a response element (TaRE) located in the region [7252/7230], with RelA acting as the transcriptional activator. Finally, we provide de®nitive evidence for the role of both TGF-b and TNF-a response elements as enhancer sequences, functioning in the context of a heterologous promoter in an additive manner in response to TGF-b and TNF-a. This study provides the ®rst identi®cation of a functional interaction between the two immediate-early transcription factors, SMAD and NFkB, to activate the expression of an extracellular matrixrelated gene, COL7A1.

Smad-dependent stimulation of type I collagen gene expression in human skin fibroblasts by TGF-β involves functional cooperation with p300/CBP transcriptional coactivators

“…Upon ligand activation, the heteromeric complex of receptorspeci®c Smad3 and Smad4 translocate into the nucleus and bind to speci®c elements in target promoters, resulting in activation of their transcription (Heldin et al, 1997). We and others have previously demonstrated that Smad3 transactivated the collagen promoter and enhanced their response to TGF-b in human primary ®broblasts (Vindevoghel et al, 1998;Kon et al, 1999;Chen et al, 1999). The mechanisms that control transactivation of collagen and other cellular genes by the DNA-bound Smad complex remain poorly understood, and are likely to involve the interaction of Smads with coactivators.…”

Smads mediate signaling of the TGFβ superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis

“…In addition, Smads may aect epidermal dierentiation via TGFb-independent pathways. Potential candidates for these TGFb-independent genes include calmodulin, NF-kB, and the vitamin D receptor, all of which have been shown to play an important role in epidermal dierentiation (Bikle and Pillai, 1988;Hu et al, 1999;Li et al, 1999;Ma et al, 1997;Roop et al, 1987;Rougui et al, 1996;Takeda et al, 1999), and to interact directly with Smads (Kon et al, 1999;Yanagisawa et al, 1999;Zimmerman et al, 1998). Therefore, it will be worthwhile to further determine the exact role of Smads in epidermal dierentiation in the future.…”

Transforming Growth Factor-β1 Inhibition of Macrophage Activation Is Mediated via Smad3

“…Most studies to date examining the function of Smad proteins in TGF-␤1 signaling have focused on genes that are transactivacted by TGF-␤1, including plasminogen activator inhibitor (PAI)-1 (27), collagen-I (28) and collagen-VII (29,30), and the cyclin-dependent kinase inhibitors p15 (31) and p21 (32,33). In contrast to TGF-␤1-mediated gene transactivation, the mechanism by which TGF-␤1 inhibits gene transcription is not well characterized.…”