Otmar Huber

Friedrich Schiller University Jena

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Ling Cai

Duke University

Kenneth A. Ohgi

University of California, San Diego

Amelie Lupp

Jena University Hospital

Michael G. Rosenfeld

Howard Hughes Medical Institute

Elisabeth H. Weiss

Children's Hospital of Richmond at VCU

Benjamin Giszas

Jena University Hospital

Rolf Kemler

Max Planck Institute of Immunobiology and Epigenetics

Hee June Choi

Worcester Polytechnic Institute

Charlie Chen

National Cheng Kung University

David W. Rose

University of California, San Diego

Cooperative Institutions

Jena University Hospital

Friedrich Schiller University Jena

Charité - Universitätsmedizin Berlin

Universitätsklinikum Würzburg

Freie Universität Berlin

University of California, Los Angeles

Schiller International University

Howard Hughes Medical Institute

Humboldt-Universität zu Berlin

Heidelberg University

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Inhibition of nitric oxide synthesis prevents nonadrenergic, noncholinergic relaxation of human esophageal circular muscle

Gastroenterology (1992)

Otmar Huber Pierangelo Geppetti C. Bertrand Nigel W. Bunnett Haile T. Debas

Circular muscle

Muscle relaxation

10.1016/0016-5085(92)91672-q

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Citations (1)

T1903 Increased Expression of Pontin in Human Colorectal Cancer Tissue

Gastroenterology (2008)

Johannes C. Lauscher Jörn Gröne Christoph Loddenkemper H. J. Buhr Hubert G. Hotz

Endoscopic submucosal dissection

Proinflammatory cytokine

10.1016/s0016-5085(08)64188-8

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Citations (0)

Pontin52, an interaction partner of β-catenin, binds to the TATA box binding protein

Proceedings of the National Academy of Sciences (1998)

Andreas Bauer Otmar Huber Rolf Kemler

β-catenin, the vertebrate homolog of the Drosophila Armadillo protein, has been shown to have dual cellular functions, as a component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. At Wnt signaling, β-catenin becomes stabilized in the cytoplasm and subsequently available for interaction with transcription factors of the lymphocyte enhancer factor-1/T-cell factor family, resulting in a nuclear localization of β-catenin. Although β-catenin does not bind DNA directly, its carboxyl- and amino-terminal regions exhibit a transactivating activity still not well understood molecularly. Here we report the identification of an interaction partner of β-catenin, a nuclear protein designated Pontin52. Pontin52 binds β-catenin in the region of Armadillo repeats 2–5 and, more importantly, also binds the TATA box binding protein. We provide evidence for an in vivo multiprotein complex composed of Pontin52, β-catenin, and lymphocyte enhancer factor-1/T-cell factor. Our results suggest involvement of Pontin52 in the nuclear function of β-catenin.

TATA box

10.1073/pnas.95.25.14787

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Citations (187)

The tumor suppressor Fhit acts as a repressor of β-catenin transcriptional activity

Proceedings of the National Academy of Sciences (2007)

Jörg Weiske Kai Frederik Albring Otmar Huber

The Fra3B locus on chromosome 3p14.2 targeting the fragile histidine triad (Fhit) gene represents one of the most common fragile sites of the human genome and is associated with early preneoplastic and malignant disorders in multiple human tumors. Fhit was classified as a tumor suppressor; however, the molecular mechanisms of its function are not well established. Here, we report that Fhit associates with the lymphoid enhancer-binding factor 1/T cell factor/beta-catenin complex by directly binding to beta-catenin, a major player in the canonical Wnt pathway that is deregulated in numerous forms of human cancer. In binding to the beta-catenin C-terminal domain, Fhit represses transcription of target genes such as cyclin D1, axin2, MMP-14, and survivin. Knockdown of Fhit reversed this effect, whereas this reversal was not detectable when beta-catenin was knocked down simultaneously. The Fhit enzymatic activity as a diadenosine-polyphosphate hydrolase is not required for the down-regulation of beta-catenin-mediated transcription as examined with an enzymatic inactive Fhit-H96N protein. ChIPs revealed recruitment of Fhit/beta-catenin complexes to target gene promoters. In soft agar assays Fhit and beta-catenin are involved in regulation of anchorage-independent growth. These observations assign to the tumor suppressor Fhit an unexpected role in the regulation of beta-catenin-mediated gene transcription.

FHIT

Chromosomal fragile site

10.1073/pnas.0703664105

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Citations (81)

Transient opening of the perineurial barrier for analgesic drug delivery

Proceedings of the National Academy of Sciences (2012)

Dagmar Hackel Susanne M. Krug Reine-Solange Sauer Shaaban A. Mousa Alexander Böcker

Selective targeting of sensory or nociceptive neurons in peripheral nerves remains a clinically desirable goal. Delivery of promising analgesic drugs is often impeded by the perineurium, which functions as a diffusion barrier attributable to tight junctions. We used perineurial injection of hypertonic saline as a tool to open the perineurial barrier transiently in rats and elucidated the molecular action principle in mechanistic detail: Hypertonic saline acts via metalloproteinase 9 (MMP9). The noncatalytic hemopexin domain of MMP9 binds to the low-density lipoprotein receptor-related protein-1, triggers phosphorylation of extracellular signal-regulated kinase 1/2, and induces down-regulation of the barrier-forming tight junction protein claudin-1. Perisciatic injection of any component of this pathway, including MMP9 hemopexin domain or claudin-1 siRNA, enables an opioid peptide ([D-Ala2, N -Me-Phe4,Gly5-ol]-enkephalin) and a selective sodium channel (NaV1.7)-blocking toxin (ProToxin-II) to exert antinociceptive effects without motor impairment. The latter, as well as the classic TTX, blocked compound action potentials in isolated nerves only after disruption of the perineurial barrier, which, in return, allowed endoneurally released calcitonin gene-related peptide to pass through the nerve sheaths. Our data establish the function and regulation of claudin-1 in the perineurium as the major sealing component, which could be modulated to facilitate drug delivery or, potentially, reseal the barrier under pathological conditions.

Perineurium

10.1073/pnas.1120800109

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Citations (87)

Author Correction: Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes

Nature (2022)

Jung Hwa Kim Bogyou Kim Ling Cai Hee June Choi Kenneth A. Ohgi

10.1038/s41586-022-04945-1

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Citations (2)

Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model

Scientific Reports (2016)

Marko Gröger Knut Rennert Benjamin Giszas Elisabeth H. Weiss J. E. Dinger

Abstract Liver dysfunction is an early event in sepsis-related multi-organ failure. We here report the establishment and characterization of a microfluidically supported in vitro organoid model of the human liver sinusoid. The liver organoid is composed of vascular and hepatocyte cell layers integrating non-parenchymal cells closely reflecting tissue architecture and enables physiological cross-communication in a bio-inspired fashion. Inflammation-associated liver dysfunction was mimicked by stimulation with various agonists of toll-like receptors. TLR-stimulation induced the release of pro- and anti-inflammatory cytokines and diminished expression of endothelial VE-cadherin, hepatic MRP-2 transporter and apolipoprotein B (ApoB), resulting in an inflammation-related endothelial barrier disruption and hepatocellular dysfunction in the liver organoid. However, interaction of the liver organoid with human monocytes attenuated inflammation-related cell responses and restored MRP-2 transporter activity, ApoB expression and albumin/urea production. The cellular events observed in the liver organoid closely resembled pathophysiological responses in the well-established sepsis model of peritoneal contamination and infection (PCI) in mice and clinical observations in human sepsis. We therefore conclude that this human liver organoid model is a valuable tool to investigate sepsis-related liver dysfunction and subsequent immune cell-related tissue repair/remodeling processes.

Organoid

10.1038/srep21868

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Citations (47)

Correction: Corrigendum: Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model

Scientific Reports (2018)

Marko Gröger Knut Rennert Benjamin Giszas Elisabeth H. Weiss J. E. Dinger

This corrects the article DOI: 10.1038/srep21868.

Biochip

Monocyte

10.1038/srep46988

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Citations (297)

Transcriptional regulation of a metastasis suppressor gene by Tip60 and β-catenin complexes

Nature (2005)

Jung Hwa Kim Bogyou Kim Ling Cai Hee June Choi Kenneth A. Ohgi

Metastasis Suppressor Gene

Metastasis suppressor

10.1038/nature03452

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Citations (291)

An α- E-catenin gene trap mutation defines its function in preimplantation development

Proceedings of the National Academy of Sciences (1997)

Miguel Torres Anastassia Stoykova Otmar Huber Kamal Chowdhury Paolo Bonaldo

Catenins are proteins associated with the cytoplasmic domain of cadherins, a family of transmembrane cell adhesion molecules. The cadherin-catenin adhesion system is involved in morphogenesis during development and in the maintenance of the integrity of different tissue types. Using a gene trap strategy, we have isolated a mouse mutation for the gene encoding the alpha-E-catenin. This form of the alpha-catenin appears frequently coexpressed with E-cadherin in epithelial cell types. The mutation obtained eliminates the carboxyl-terminal third of the protein but nevertheless provokes a complete loss-of-function phenotype. Homozygous mutants show disruption of the trophoblast epithelium (the first differentiated embryonic tissue), and development is consequently blocked at the blastocyst stage. This phenotype parallels the defects observed in E-cadherin mutant embryos. Our results show the requirement of the alpha-E-catenin carboxy terminus for its function and represent evidence of the role of the alpha-E-catenin in vivo, identifying this molecule as the natural partner of the E-cadherin in trophoblast epithelium.

Trophoblast

10.1073/pnas.94.3.901

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Citations (215)