Fitting a xenobiotic receptor into cell homeostasis: How the dioxin receptor interacts with TGFβ signaling
Introduction
Transforming growth factor beta (TGFβ) is a pleiotropic extracellular cytokine that has concentrated much attention due to its prominent role in development, tissue homeostasis and wound healing [1], vasculogenesis [2] and in the progression of frequent diseases such as organ fibrosis, autoimmunity and tumor development [3], [4], [5]. Because of these diverse functions, and considering that the response to TGFβ largely depends on the phenotype and the microenvironment of the target cell, a great deal of effort is underway to precisely define the signaling networks and the intermediate molecules that fit the TGFβ response to each individual cell type. It is therefore of great importance to determine the upstream molecular pathways that regulate TGFβ expression and activation and those downstream that propagates the signal to the cell nucleus in a cell-specific context. The dioxin receptor (AhR), a well-conserved transcription factor constitutively expressed in most cell types, has been recently linked to endogenous cell functions that control proliferation, differentiation, migration, development, tissue homeostasis, vasculogenesis and cancer [6], [7], [8], [9], [10], [11].
It is remarkable that AhR and TGFβ seem to converge to the regulation of the same cellular processes, which suggest a potential connection between their respective signaling pathways. Indeed, in vitro and in vivo analyses in cell systems and in mouse models lacking AhR expression (AhR−/−) have demonstrated that AhR is relevant to maintain the endogenous levels of TGFβ activity, and that the up-regulation of this cytokine could have a role in producing some of the phenotypes identified in AhR−/− mice. It is therefore reasonable to assume that the transcriptional activity of AhR, whether by a direct effect on TGFβ expression/activation and/or by the regulation of intermediate proteins, contributes to modulate physiological processes involving TGFβ. Equally relevant is the potential implication of AhR in regulating TGFβ activity under pathological conditions. Since the mechanisms controlling TGFβ synthesis and activation in the ECM are largely unknown, and because this cytokine is important for different human diseases, its functional interaction with AhR makes this receptor an interesting partner in TGFβ-dependent functions. On the long term, the study of human diseases in which TGFβ has a relevant role could emphasize AhR as a genetic marker with potential clinical relevance. This review will summarize the current status of the AhR-TGFβ relationship from the regulatory and functional point of views and an attempt will be made to integrate TGFβ in some phenotypes caused by the lack of AhR expression in vivo.
Section snippets
The dioxin receptor in the interphase between toxicity and development
The helix-loop-helix (HLH) family of proteins comprises transcriptional regulators that bind to DNA through a basic domain located at their amino terminus. In metazoans, the so-called basic-helix-loop-helix (bHLH) transcription factors regulate many processes including myogenesis, neurogenesis, hematopoiesis, circadian rhythms, metabolism and organ development [12], [13]. bHLH proteins have been grouped in seven classes attending to their sequence similarity, tissue distribution, DNA-binding
Functional cross-talk between AhR and TGFβ
AhR has a role in modulating TGFβ expression and activity in cell culture and in vivo. However, the regulatory pathway is probably more complex since TGFβ also alters AhR mRNA expression in certain cell lines.
AhR as a repressor of constitutive LTBP-1 expression: role of epigenetics
The human LTBP-1L and -1S isoforms are expressed in a cell-specific manner and genomic sequencing of the human Ltbp-1 gene promoter revealed that Ltbp-1L is produced by alternative splicing to an internal acceptor site in exon 1 of Ltbp-1S[53]. An analogous tissue-specific pattern of expression has been described in mouse where LTBP-1L and -1S are produced by two alternatively spliced transcripts from a single Ltbp-1 gene [57], [98]. These studies led to the isolation of the 5′ upstream
Concluding remarks
An important conclusion that can be extracted from studies dealing with AhR and TGFβ is that both molecules interact, and perhaps converge, to the regulation of common signaling pathways that modulate important cellular functions such as proliferation, differentiation, migration, vasculogenesis, wound healing, fibrosis and tumor development. It is clear that AhR and TGFβ are subjected to a reciprocal regulatory mechanism that mutually represses each other’s expression. While this is an
Acknowledgments
This manuscript has been funded by Grants SAF2002-0034 and SAF2005-00130 from the Spanish Ministry of Education and Sciences (to P.M.F.-S.). A.G.-D. and J.M.C.-G. were fellows from the Spanish Ministry of Education and Sciences and from the Junta de Extremadura, respectively.
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