Fitting a xenobiotic receptor into cell homeostasis: how the dioxin receptor interacts with TGFbeta signaling.

Abstract:

:As our knowledge on the mechanisms that control cell function increases, more complex signaling pathways and quite intricate cross-talks among regulatory proteins are discovered. Establishing accurate interactions between cellular networks is essential for a healthy cell and different alterations in signaling are known to underline human disease. Transforming growth factor beta (TGFbeta) is an extracellular cytokine that regulates such critical cellular responses as proliferation, apoptosis, differentiation, angiogenesis and migration, and it is assumed that the latency-associated protein LTBP-1 plays a relevant role in TGFbeta targeting and activation in the extracellular matrix (ECM). The dioxin receptor (AhR) is a unique intracellular protein long studied because of its critical role in xenobiotic-induced toxicity and carcinogenesis. Yet, a large set of studies performed in cellular systems and in vivo animal models have suggested important xenobiotic-independent functions for AhR in cell proliferation, differentiation and migration and in tissue homeostasis. Remarkably, AhR activity converges with TGFbeta-dependent signaling through LTBP-1 since cells lacking AhR expression have phenotypic alterations that can be explained, at least in part, by the coordinated regulation of both proteins. Here, we will discuss the existence of functional interactions between AhR and TGFbeta signaling. We will focus on regulatory and functional aspects by analyzing how AhR status determines TGFbeta activity and by proposing a mechanism through which LTBP-1, a novel AhR target gene, mediates such effects. We will integrate ECM proteases in the AhR-LTBP-1-TGFbeta axis and suggest a model that could help explain some in vivo phenotypes associated to AhR deficiency.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Gomez-Duran A,Carvajal-Gonzalez JM,Mulero-Navarro S,Santiago-Josefat B,Puga A,Fernandez-Salguero PM

doi

10.1016/j.bcp.2008.08.032

subject

Has Abstract

pub_date

2009-02-15 00:00:00

pages

700-12

issue

4

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(08)00555-8

journal_volume

77

pub_type

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