bcn-1 Element-dependent Activation of the Laminin γ1 Chain Gene by the Cooperative Action of Transcription Factor E3 (TFE3) and Smad Proteins

Abstract

Laminin is a major component of the extracellular matrix. The laminin ␥1 chain is the least variant component of the laminin heterotrimeric assembly. The laminin ␥1 chain gene (LAMC1) expression is induced by several factors, including transforming growth factor-␤ (TGF-␤). LAMC1 promoter contains a highly conserved transcriptional element, bcn-1. We screened cDNA libraries with the yeast one-hybrid system to identify transcriptional factors that are recognized by the bcn-1 motif. Using this strategy we isolated the basic helixloop-helix/leucine zipper (bHLHzip) E-box-binding transcription factor, TFE3. Until now, the E-box was the only element known to recruit the bHLHzip transcription factors. Although the bcn-1 element only remotely resembles the E-box sequence, we show that TFE3 binds and activates the bcn-1 element. TFE3 cooperates with Smad proteins in the activation of the LAMC1 promoter in cells, an effect that is critically dependent not only on the bcn-1 element but also on one of the Smad-binding elements (SBE). The cooperative induction of the LAMC1 promoter and the endogenous LAMC1 gene by TFE3 and Smad3 is augmented by the TGF-␤ signaling pathway. Thus, the bcn-1 is a novel TFE3-dependent TGF-␤ target element that regulates LAMC1 gene expression.

Both Max and TFE3 Cooperate with Smad Proteins to Bind the Plasminogen Activator Inhibitor-1 Promoter, but They Have Opposite Effects on Transcriptional Activity

“…TFE3 and Smad3 can synergistically activate the transcription of PAI-1, Smad7, and laminin ␥1 chain genes (25,26,28,60). The present results demonstrate that other bHLZHIP proteins, including TFEB and Max, can also interact with Smads and influence their transcriptional activities.…”

“…Because TFE3 and Max are distantly related within the bHLHZIP family, it is likely that Smads can interact with many, and perhaps all bHLHZIP family members. It was recently suggested that the laminin promoter can be regulated by Smad interactions with both TFE3 and USF1 (60). Smads have also been shown to interact with Myc, although the interaction interface identified in those studies is outside the conserved bHLHZIP region (29).…”

Increase in laminin expression in allergic airway remodelling and decrease by dexamethasone

“…Prior work by LEE et al [32] demonstrated that IL-13 induces lung fibrosis in mice by selective activation of transforming growth factor-b (TGF-b). TGF-b induces expression of laminin a1 chains in rat mesangial cells [33] and laminin c1 chains in mouse distal respiratory epithelial cells [34]. The ability of laminin, via a laminin/nidogen binding site, to form a lattice-type assembly with collagen in the lung matrix may lead to airway wall thickening.…”

TGF-β signal transduction and mesangial cell fibrogenesis

“…With the use of a yeast one-hybrid approach, the TFE3 transcription factor was cloned from a rat mesangial cell cDNA library, indicating that this basic helix-loop-helix/leucine zipper transcription factor binds to bcn-1. Stimulation of bcn-1 by TGF-␤ to activate the LAMC1 promoter was enhanced by overexpression of Smad3 and was dependent on the Smadbinding element in the LAMC1 promoter (45). In addition, a similar strategy identified binding of the gut-enriched Kruppel-like factor (GKLF) to bcn-1.…”

“…Further insight into these events is provided by elegant studies of laminin-␥ 1 gene regulation by Bomsztyk and colleagues (33,45). The LAMC1 promoter contains a highly conserved transcriptional element, termed bcn-1.…”