Institute for Cell Biology

Münster, Germany

Institute for Cell Biology

Münster, Germany
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News Article | April 21, 2017
Site: www.eurekalert.org

Early in evolution, sugar intake and the regulation of life span were linked with each other. The hormone insulin is crucial here. It reduces blood sugar levels by binding to its receptor on the cell surface. However, many processes for stress management and survival are shut down at the same time. When there is a good supply of food, they appear unnecessary to the organism, although this reduces life expectancy over the long term. The insulin receptor thus acts like a brake on life expectancy. Genetically altered laboratory animals in which the insulin receptor no longer functions actually live much longer than normal. But how is the insulin receptor normally kept in check in our cells and tissue? A recent study by scientists at the Universities of Cologne and Bonn answers this fundamental question. The team of researchers shows that the protein CHIP plays a crucial role here. It acts like a disposal helper, in that it supplies the insulin receptor to the cellular breakdown and recycling systems by affixing a "green dot" in the form of the molecule ubiquitin onto the receptor. The life expectancy brake is thus released and CHIP unfurls anti-aging activity. "CHIP fulfils this function in nematodes, as well as in fruit flies and in humans. This makes the protein so interesting for us," explains Prof. Thorsten Hoppe, one of the two lead authors of the study from the Cluster of Excellence CECAD at the University of Cologne. When CHIP is missing, it leads to premature aging The findings were initially very surprising, as CHIP had so far been associated with completely different breakdown processes. Specifically, CHIP also disposes of faulty and damaged proteins, which increasingly occur at an older age and the accumulation of which leads to dementia and muscle weakness. The researchers actually recreated such degenerative illnesses in the nematode and in human cells and observed that there was no longer enough CHIP available to break down the insulin receptor. Premature aging is the result. Can the dream of a fountain of youth be made a reality and life extended in that researchers encourage cells to form more CHIP? "Unfortunately, it's not that easy," says lead author Prof. Jörg Höhfeld from the Institute for Cell Biology at the University of Bonn. When there is too much CHIP, undamaged proteins are also recycled and the organism is weakened. However, the researchers are already looking for mechanisms that control CHIP when breaking down the insulin receptor and that could one day also be used for new treatments. Publication: The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover, "Cell", DOI: 10.1016/j.cell.2017.04.003 Prof. Thorsten Hoppe CECAD Cologne and Institute for Genetics University of Cologne Tel. +49 221/47884218 E-mail: thorsten.hoppe@uni-koeln.de


News Article | April 25, 2017
Site: www.medicalnewstoday.com

Not only does our way of life determine how long we live but so too does our genetic material. Of particular importance here is a genetic program that is controlled by the insulin receptor. A team of researchers from the Universities of Cologne and Bonn has now discovered how protein aggregation affects this genetic program and thus triggers aging. The results have now been published in the journal Cell. Early in evolution, sugar intake and the regulation of life span were linked with each other. The hormone insulin is crucial here. It reduces blood sugar levels by binding to its receptor on the cell surface. However, many processes for stress management and survival are shut down at the same time. When there is a good supply of food, they appear unnecessary to the organism, although this reduces life expectancy over the long term. The insulin receptor thus acts like a brake on life expectancy. Genetically altered laboratory animals in which the insulin receptor no longer functions actually live much longer than normal. But how is the insulin receptor normally kept in check in our cells and tissue? A recent study by scientists at the Universities of Cologne and Bonn answers this fundamental question. The team of researchers shows that the protein CHIP plays a crucial role here. It acts like a disposal helper, in that it supplies the insulin receptor to the cellular breakdown and recycling systems by affixing a "green dot" in the form of the molecule ubiquitin onto the receptor. The life expectancy brake is thus released and CHIP unfurls anti-aging activity. "CHIP fulfils this function in nematodes, as well as in fruit flies and in humans. This makes the protein so interesting for us," explains Prof. Thorsten Hoppe, one of the two lead authors of the study from the Cluster of Excellence CECAD at the University of Cologne. The findings were initially very surprising, as CHIP had so far been associated with completely different breakdown processes. Specifically, CHIP also disposes of faulty and damaged proteins, which increasingly occur at an older age and the accumulation of which leads to dementia and muscle weakness. The researchers actually recreated such degenerative illnesses in the nematode and in human cells and observed that there was no longer enough CHIP available to break down the insulin receptor. Premature aging is the result. Can the dream of a fountain of youth be made a reality and life extended in that researchers encourage cells to form more CHIP? "Unfortunately, it's not that easy," says lead author Prof. Jörg Höhfeld from the Institute for Cell Biology at the University of Bonn. When there is too much CHIP, undamaged proteins are also recycled and the organism is weakened. However, the researchers are already looking for mechanisms that control CHIP when breaking down the insulin receptor and that could one day also be used for new treatments. Article: The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover, Thorsten Hoppe et al., Cell, doi: 10.1016/j.cell.2017.04.003, published 20 April 2017.


News Article | December 8, 2016
Site: www.eurekalert.org

The German Research Foundation (DFG) will be providing financial support to the Collaborative Research Center (CRC) 1080 on "Molecular and cellular mechanisms of neuronal homeostasis" for four more years. In addition to Johannes Gutenberg University Mainz (JGU), Goethe University Frankfurt as the CRC's speaker university, the Max Planck Institute for Brain Research, and the Mainz-based Institute of Molecular Biology (IMB) are participating in this research center. A total of some EUR 12 million is being made available in the new funding period that will commence on January 1, 2017. CRC 1080 was established on January 1, 2013 with Johannes Gutenberg University Mainz acting as the speaker university. With the commencement of the new funding phase, the speaker role will be transferred to Frankfurt University which, as a member of the Rhine-Main Neuroscience Network (rmn²), is participating in the CRC with its own research projects. The future coordinator of the CRC, Professor Amparo Acker-Palmer, heads up the Frankfurt Institute for Cell Biology and Neurosciences and is also a fellow of the Gutenberg Research College (GRC) at JGU. Professor Heiko Luhmann, Director of the Institute of Physiology at the Mainz University Medical Center, will take up the post of deputy coordinator. The purpose of the CRC on "Molecular and cellular mechanisms of neuronal homeostasis" is to study the molecular and cellular interactions that enable the brain to maintain a state of functional equilibrium, otherwise known as network homeostasis. New findings should contribute to understanding disease processes in the brain, thus providing insights in the development of innovative new therapies. This might even include the creation of new pharmaceutical agents that could be used to treat cerebral disorders in humans. Specifically, the researchers working at the CRC are investigating different classes of molecules, such as those involved in the control of cell-to-cell interactions and signaling processes. "The extension of funding of the Collaborative Research Center 1080, which studies aspects that offer great potential benefits to society, owes much to our very productive and collaborative research endeavors," pointed out the Chief Scientific Officer of the Mainz University Medical Center, Professor Ulrich Förstermann.


Gross-Thebing T.,Institute for Cell Biology | Paksa A.,Institute for Cell Biology | Raz E.,Institute for Cell Biology
BMC Biology | Year: 2014

Background: Whole-mount in situ hybridization (WISH) is a fundamental tool for studying the spatio-temporal expression pattern of RNA molecules in intact embryos and tissues. The available methodologies for detecting mRNAs in embryos rely on enzymatic activities and chemical reactions that generate diffusible products, which are not fixed to the detected RNA, thereby reducing the spatial resolution of the technique. In addition, current WISH techniques are time-consuming and are usually not combined with methods reporting the expression of protein molecules.Results: The protocol we have developed and present here is based on the RNAscope technology that is currently employed on formalin-fixed, paraffin-embedded and frozen tissue sections for research and clinical applications. By using zebrafish embryos as an example, we provide a robust and rapid method that allows the simultaneous visualization of multiple transcripts, demonstrated here for three different RNA molecules. The optimized procedure allows the preservation of embryo integrity, while exhibiting excellent signal-to-noise ratios. Employing this method thus allows the determination of the spatial expression pattern and subcellular localization of multiple RNA molecules relative to each other at high resolution, in the three-dimensional context of the developing embryo or tissue under investigation. Lastly, we show that this method preserves the function of fluorescent proteins that are expressed in specific cells or cellular organelles and conserves antigenicity, allowing protein detection using antibodies.Conclusions: By fine-tuning the RNAscope technology, we have successfully redesigned the protocol to be compatible with whole-mount embryo samples. Using this robust method for zebrafish and extending it to other organisms would have a strong impact on research in developmental, molecular and cell biology. Of similar significance would be the adaptation of the method to whole-mount clinical samples. Such a protocol would contribute to biomedical research and clinical diagnostics by providing information regarding the three-dimensional expression pattern of clinical markers. © 2014 Gross-Thebing et al.; licensee BioMed Central Ltd.


Kardash E.,Institute for Cell Biology | Reichman-Fried M.,Institute for Cell Biology | Maitre J.L.,Institute for Cell Biology | Boldajipour B.,Institute for Cell Biology | And 4 more authors.
Nature cell biology | Year: 2010

Cell migration is central to embryonic development, homeostasis and disease, processes in which cells move as part of a group or individually. Whereas the mechanisms controlling single-cell migration in vitro are relatively well understood, less is known about the mechanisms promoting the motility of individual cells in vivo. In particular, it is not clear how cells that form blebs in their migration use those protrusions to bring about movement in the context of the three-dimensional cellular environment. Here we show that the motility of chemokine-guided germ cells within the zebrafish embryo requires the function of the small Rho GTPases Rac1 and RhoA, as well as E-cadherin-mediated cell-cell adhesion. Using fluorescence resonance energy transfer we demonstrate that Rac1 and RhoA are activated in the cell front. At this location, Rac1 is responsible for the formation of actin-rich structures, and RhoA promotes retrograde actin flow. We propose that these actin-rich structures undergoing retrograde flow are essential for the generation of E-cadherin-mediated traction forces between the germ cells and the surrounding tissue and are therefore crucial for cell motility in vivo.


Martin M.,Institute of Human Genetics | Martin M.,TU Dortmund | Masshofer L.,University of Duisburg - Essen | Temming P.,University of Duisburg - Essen | And 9 more authors.
Nature Genetics | Year: 2013

Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625. © 2013 Nature America, Inc. All rights reserved.


Senyurek I.,University of Tübingen | Kempf W.E.,University of Tübingen | Klein G.,University Medical Clinic | Maurer A.,University of Tübingen | And 10 more authors.
Journal of Innate Immunity | Year: 2014

Laminins play a fundamental role in basement membrane architecture and function in human skin. The C-terminal laminin G domain-like (LG) modules of laminin α chains are modified by proteolysis to generate LG1-3 and secreted LG4-5 tandem modules. In this study, we provide evidence that skin-derived cells process and secrete biologically active peptides from the LG4-5 module of the laminin α3, α4 and α5 chain in vitro and in vivo. We show enhanced expression and processing of the LG4-5 module of laminin α3 in keratinocytes after infection and in chronic wounds in which the level of expression and further processing of the LG4-5 module correlated with the speed of wound healing. Furthermore, bacterial or host-derived proteases promote processing of laminin α3 LG4-5. On a functional level, we show that LG4-5-derived peptides play a role in wound healing. Moreover, we demonstrate that LG4-derived peptides from the α3, α4 and α5 chains have broad antimicrobial activity and possess strong chemotactic activity to mononuclear cells. Thus, the data strongly suggest a novel multifunctional role for laminin LG4-5-derived peptides in human skin and its involvement in physiological processes and pathological conditions such as inflammation, chronic wounds and skin infection. © 2014 S. Karger AG, Basel.


Kardash E.,Institute for Cell Biology | Reichman-Fried M.,Institute for Cell Biology | Matre J.-L.,Max Planck Institute of Molecular Cell Biology and Genetics | Boldajipour B.,Institute for Cell Biology | And 4 more authors.
Nature Cell Biology | Year: 2010

Cell migration is central to embryonic development, homeostasis and disease, processes in which cells move as part of a group or individually. Whereas the mechanisms controlling single-cell migration in vitro are relatively well understood, less is known about the mechanisms promoting the motility of individual cells in vivo. In particular, it is not clear how cells that form blebs in their migration use those protrusions to bring about movement in the context of the three-dimensional cellular environment. Here we show that the motility of chemokine-guided germ cells within the zebrafish embryo requires the function of the small Rho GTPases Rac1 and RhoA, as well as E-cadherin-mediated cell-cell adhesion. Using fluorescence resonance energy transfer we demonstrate that Rac1 and RhoA are activated in the cell front. At this location, Rac1 is responsible for the formation of actin-rich structures, and RhoA promotes retrograde actin flow. We propose that these actin-rich structures undergoing retrograde flow are essential for the generation of E-cadherin-mediated traction forces between the germ cells and the surrounding tissue and are therefore crucial for cell motility in vivo. © 2010 Macmillan Publishers Limited. All rights reserved.


PubMed | Max Planck Institute for Biophysical Chemistry, Weizmann Institute of Science, Max Planck Institute for Molecular Biomedicine, French National Center for Scientific Research and Institute for Cell Biology
Type: | Journal: Nature communications | Year: 2016

The precise positioning of organ progenitor cells constitutes an essential, yet poorly understood step during organogenesis. Using primordial germ cells that participate in gonad formation, we present the developmental mechanisms maintaining a motile progenitor cell population at the site where the organ develops. Employing high-resolution live-cell microscopy, we find that repulsive cues coupled with physical barriers confine the cells to the correct bilateral positions. This analysis revealed that cell polarity changes on interaction with the physical barrier and that the establishment of compact clusters involves increased cell-cell interaction time. Using particle-based simulations, we demonstrate the role of reflecting barriers, from which cells turn away on contact, and the importance of proper cell-cell adhesion level for maintaining the tight cell clusters and their correct positioning at the target region. The combination of these developmental and cellular mechanisms prevents organ fusion, controls organ positioning and is thus critical for its proper function.


PubMed | Leiden University and Institute for Cell Biology
Type: Journal Article | Journal: Disease models & mechanisms | Year: 2016

Triple-negative breast cancer (TNBC) is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

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