Somatic mutation and SNP in the promoter of dbpA and human hepatocarcinogenesis

Hayashi, J.; Kajino, Kazunori; Umeda, Takuro; Takano, Seigo; Arakawa, Yasuyuki; Kudo, Masatoshi; Hino, Okio

doi:10.3892/ijo.21.4.847

Cited by 21 publications

(30 citation statements)

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“…The ZONAB-dependent survival pathway thus provides a possible therapeutic opportunity to target ZONAB to induce cell death in cancer cells. This survival pathway seems up-regulated in different types of carcinomas because ZONAB has been reported to be upregulated in cancers form different tissues (14)(15)(16)(17)(18)(19)(20). Therapeutic targeting of ZONAB might also improve the effectiveness of existing therapies, because depletion enhanced cell death in response to Taxol (Fig.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

“…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%

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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“…In tumors such mutually exclusive alterations are found frequently for genes/proteins that are involved in a similar signaling pathway (32,33), suggesting that overexpression of symplekin or ZONAB could have similar consequences for tumorigenesis. Although E2F1-mediated transcriptional stimulation (34), as well as the presence of mutations and polymorphism in the ZONAB/ DbpA promoter (35), has been suggested as a cause for the increased transcriptional activity detected in hepatocarcinoma, the reasons underlying symplekin overexpression remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Büchert

Papin

Bonnans

et al. 2010

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

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Symplekin is a ubiquitously expressed protein involved in cytoplasmic RNA polyadenylation and transcriptional regulation and is localized at tight junctions (TJs) in epithelial cells. Nuclear symplekin cooperates with the Y-box transcription factor zonula occludens 1-associated nucleic acid-binding protein (ZONAB) to increase the transcription of cell cycle-related genes and also inhibits differentiation of intestinal cells. We detected high levels of nuclear symplekin in 8 of 12 human colorectal cancer (CRC) samples. shRNAmediated reduction of symplekin expression was sufficient to decrease significantly the anchorage-independent growth and proliferation of HT-29 CRC cells as well as their tumorigenicity when injected into immunodeficient animals. Symplekin downregulation also was found to alter ion transport through TJs, to promote the localization of ZONAB in the membrane rather than the nucleus, and strongly to enhance cell polarization in a 3D matrix, leading to the formation of spheroids organized around a central lumen. Claudin-2 expression was reduced following symplekin down-regulation, an effect mimicked when ZONAB expression was down-regulated using selective siRNA. Virus-mediated restoration of claudin-2 expression was found to restore nuclear expression of ZONAB in HT29ΔSym cells and to rescue the phenotypic alterations induced by symplekin down-regulation of cell polarity, paracellular transport, ZONAB localization, cyclin D1 expression, proliferation, and anchorage-independent growth. Finally, siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization, similar to observations in symplekindepleted cells. Our results suggest that nuclear overexpression of symplekin promotes tumorigenesis in the human colon and that the regulation of claudin-2 expression is instrumental in this effect.polarity | transcription | tumorigenesis | colorectal | tight junctions

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“…Similarly, several junctional scaffolding proteins are bound and inactivated by viral oncogenes (Glaunsinger et al, 2001;Latorre et al, 2005). By contrast, ZONAB and its activating protein Apg2 are both upregulated in hepatocellular carcinomas, which suggests that this proliferationpromoting pathway is stimulated (Arakawa et al, 2004;Gotoh et al, 2004;Hayashi et al, 2002).…”

Section: Tjs In Diseasementioning

confidence: 99%