The Y‐box factor ZONAB/DbpA associates with GEF‐H1/Lfc and mediates Rho‐stimulated transcription

Nie, Min; Aijaz, Saima; San, Isabelle V. Leefa Chong; Balda, María S.; Matter, Karl

doi:10.1038/embor.2009.182

Cited by 50 publications

(56 citation statements)

References 26 publications

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“…Both proteins, after specific stimulus, localize in the nucleus and bind to specific promoters containing an inverted CCAAT box (Y-box). The Y-box is present in the promoters of genes encoding HER2 and several cell cycle regulators, which operate in a cell density-dependent manner [5,36,37]. Transepithelial resistance and paracellular permeability studies in human vascular endothelial (HUVEC) cell monolayers overexpressing ZO-1 and/or ZONAB demonstrated that the two proteins functionally interact at the HER2 promoter [38], suggesting that they might be part of a signaling system that could regulate epithelial differentiation, proliferation, and paracellular permeability in normal and transformed cells.…”

Section: Discussionmentioning

confidence: 99%

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

et al. 2014

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Tumor cells utilize inappropriate epithelialmesenchymal transition (EMT) mechanisms during the invasive process. It is becoming increasingly clear that estradiol (E2) induces breast cancer cell progression and enhances EMT; however, the mechanisms associated with this are unclear. We investigated the role of E2 on the expression and intracellular localization of the tight junction (TJ)-associated proteins, zonula occluden 1 (ZO-1), ZO-1-associated nucleic acid binding (ZONAB), and occludin, on the activation of cSrc and human epidermal growth factor receptor 2 (HER2) expression and cellular migration in the estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. WeNovelty and Impact Statements We demonstrated that estrogen is able to induce tight junction (TJ) disruption in two breast cancer cell lines through the activation of c-Src. Ablated expression of the novel epithelial marker CRB3 could lead to increased cell migration. Based on our findings, we propose a novel estrogen-induced TJ pathway associated with breast cancer cell motility and, eventually, to metastasis. demonstrated that 1 nM E2 elicits c-Src activation after 15 min. The p-Src/ZO-1 complex led to ZO-1 and ZONAB disruption at the TJ and increased expression of HER2 mRNAs. These changes correlate with decreased expression of the epithelial markers occludin and CRB3 and increased synthesis of N-cadherin. This led to increased MCF-7 cell migration induced by E2, even in the presence of a cell proliferation inhibitor. Incubation with ICI 182,780 (Fulvestrant), an ER antagonist, precluded the effects of E2 on c-Src phosphorylation, p-Src/ZO-1 complex formation, ZO-1/ZONAB nuclear translocation, and migration of MCF-7 cells. Our findings suggest that E2 promotes TJ disruption during tumor progression and increases cell motility. We propose a novel pathway where estrogens promote EMTassociated mechanisms that possibly lead to metastasis.

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Section: Discussionmentioning

confidence: 99%

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

et al. 2014

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“…CFTR, the transmembrane protein linked to cystic fibrosis, binds and stabilises ZO-1, leading to reduced ZO-1 expression in its absence and, thereby, promoting nuclear translocation of ZONAB, induction of cyclin D1 and repression of ErbB2 147 . Manipulation of other junctional transmembrane proteins, such as BVES, regulates ZONAB activation via a GEF-H1/RhoA-stimulated mechanism 140,148 . In endothelial cells of the blood-tumour-barrier, bradykinin-induced activation of nitric oxide synthesis induces increased permeability and ZONAB activation, leading to repression of claudin-5 and occludin promoters 149 .…”

Section: Signalling From Tight Junctionsmentioning

confidence: 99%

Tight junctions: from simple barriers to multifunctional molecular gates

Zihni

Mills

Matter

et al. 2016

Nat Rev Mol Cell Biol

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Main body of text: 5983 words 2Epithelia and endothelia separate different tissue compartments and protect multicellular organisms form the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Here, we discuss recent advances in our understanding of the molecular architecture and cellular functions of tight junctions.Microscopists in the 19 th century described the paracellular space between neighbouring cells within an epithelial sheet to be sealed by a "terminal bar", a structure later resolved by electron microscopy into a composite of distinct cell-cell junctions that is now called the epithelial junctional complex and is formed by tight junctions, adherens junctions and desmosomes 1,2 . As the former two junctions are more tightly associated and often reside at the apical end of the lateral membrane, they are often referred to as the apical junctional complex (however, in endothelia, tight junctions and adherens junctions can be intercalated) (Fig. 1). Tight junctions are essential for barrier formation, and their primary physiological role is to function as paracellular gates that restrict diffusion on the basis of size and charge. Selective paracellular diffusion is an essential process for the maintenance of homoeostasis in organs and tissues. Tight junctions have long been the most enigmatic of all adhesion complexes and eluded a detailed molecular and functional analysis due to their complex architecture. Recent years have witnessed the identification of a large array of components associated with tight junctions implicating these junctions in an unexpected range of different functions, thereby challenging the traditional model, in which tight junctions are considered a simple diffusion barrier formed by a rigid molecular complex. In line with these various functions, mutations in genes encoding tight junction proteins have been linked to a range of inherited human diseases. Additionally, tight junction components are known to be targeted by a number of pathogenic bacteria and viruses, which hijack tight junction proteins to enter and infect cells, or target junctional signalling mechanisms to cross tissue barriers. Although tight junctions are a vertebrate junction, many of their components and functions are evolutionarily conserved (Box 1).The main purpose of this review is to examine the recent advances in the unravelling of the molecular architecture of tight junctions and understanding their functions. We will discuss recent exciting insights into how tight junctions function as signalling platforms that guide cell behaviour and differen...

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“…A transcription factor activated by Rho signaling is ZO-1-associated nucleic acid binding protein (ZONAB)/DbpA, a member of the Y-box family of multifunctional nucleic acid binding proteins (10)(11)(12)(13). ZONAB is activated in different types of cancers (14)(15)(16)(17)(18)(19)(20); hence, it would be important to know whether and how ZONAB promotes cell survival in response to cytotoxic stress and proinflammatory signals because targeting such survival pathways offers therapeutic benefits.…”

mentioning

confidence: 99%

“…In epithelial cells, ZONAB associates with tight junctions by binding to ZO-1, a negative regulator, and its transcriptional activity is stimulated by GEF-H1, a RhoA exchange factor (10,11). The transcriptional activity of ZONAB is also suppressed by binding to activated RalA in the cytoplasm downstream of Ras activation (21).…”

mentioning

confidence: 99%

“…The transcriptional activity of ZONAB is also suppressed by binding to activated RalA in the cytoplasm downstream of Ras activation (21). GEF-H1 is activated by different stimuli including TNFα, EGF receptor and Erk signaling, and mechanical and environmental stress (11,(22)(23)(24). Although Y-box factors are multifunctional proteins that can bind RNA in vitro and have been proposed to function as general translational repressors (12,13,25), physiological relevance and targets of this mechanism are unclear.…”

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confidence: 99%

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Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

Nie

Balda

Matter

2012

Proc. Natl. Acad. Sci. U.S.A.

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A central component of the cellular stress response is p21 WAF1/CIP1 , which regulates cell proliferation, survival, and differentiation. Inflammation and cell stress often up-regulate p21 posttranscriptionally by regulatory mechanisms that are poorly understood. ZO-1-associated nucleic acid binding protein (ZONAB)/DbpA is a Y-box transcription factor that is regulated by components of intercellular junctions that are affected by cytokines and tissue damage. We therefore asked whether ZONAB activation is part of the cellular stress response. Here, we demonstrate that ZONAB promotes cell survival in response to proinflammatory, hyperosmotic, and cytotoxic stress and that stress-induced ZONAB activation involves the Rho regulator GEF-H1. Unexpectedly, stress-induced ZONAB activation does not stimulate ZONAB's activity as a transcription factor but leads to the posttranscriptional up-regulation of p21 protein and mRNA. Up-regulation is mediated by ZONAB binding to specific sites in the 3′-untranslated region of the p21 mRNA, resulting in mRNA stabilization and enhanced translation. Binding of ZONAB to mRNA is activated by GEF-H1 via Rho stimulation and also mediates Ras-induced p21 expression. We thus identify a unique type of stress and Rho signaling activated pathway that drives mRNA stabilization and translation and links the cellular stress response to p21 expression and cell survival.epithelia | RhoGTPases | tight junction | necrosis | apoptosis C ells developed regulatory pathways that are activated in response to proinflammatory challenges, adverse extracellular conditions, and cytotoxic stress to ensure cell survival and tissue integrity. These pathways regulate expression of genes encoding factors required to cope with stress conditions and involve transcription factors that stimulate the synthesis of mRNAs encoding proteins required for specific responses. However, expression of many crucial stress-induced genes is regulated posttranscriptionally by mechanisms that are not well understood.A central regulator of cell proliferation and survival is p21 WAF1/CIP1

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The Y‐box factor ZONAB/DbpA associates with GEF‐H1/Lfc and mediates Rho‐stimulated transcription

Cited by 50 publications

References 26 publications

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

Tight junctions: from simple barriers to multifunctional molecular gates

Stress- and Rho-activated ZO-1–associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival

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