@phdthesis{6891, abstract = {While cells of mesenchymal or epithelial origin perform their effector functions in a purely anchorage dependent manner, cells derived from the hematopoietic lineage are not committed to operate only within a specific niche. Instead, these cells are able to function autonomously of the molecular composition in a broad range of tissue compartments. By this means, cells of the hematopoietic lineage retain the capacity to disseminate into connective tissue and recirculate between organs, building the foundation for essential processes such as tissue regeneration or immune surveillance. Cells of the immune system, specifically leukocytes, are extraordinarily good at performing this task. These cells are able to flexibly shift their mode of migration between an adhesion-mediated and an adhesion-independent manner, instantaneously accommodating for any changes in molecular composition of the external scaffold. The key component driving directed leukocyte migration is the chemokine receptor 7, which guides the cell along gradients of chemokine ligand. Therefore, the physical destination of migrating leukocytes is purely deterministic, i.e. given by global directional cues such as chemokine gradients. Nevertheless, these cells typically reside in three-dimensional scaffolds of inhomogeneous complexity, raising the question whether cells are able to locally discriminate between multiple optional migration routes. Current literature provides evidence that leukocytes, specifically dendritic cells, do indeed probe their surrounding by virtue of multiple explorative protrusions. However, it remains enigmatic how these cells decide which one is the more favorable route to follow and what are the key players involved in performing this task. Due to the heterogeneous environment of most tissues, and the vast adaptability of migrating leukocytes, at this time it is not clear to what extent leukocytes are able to optimize their migratory strategy by adapting their level of adhesiveness. And, given the fact that leukocyte migration is characterized by branched cell shapes in combination with high migration velocities, it is reasonable to assume that these cells require fine tuned shape maintenance mechanisms that tightly coordinate protrusion and adhesion dynamics in a spatiotemporal manner. Therefore, this study aimed to elucidate how rapidly migrating leukocytes opt for an ideal migratory path while maintaining a continuous cell shape and balancing adhesive forces to efficiently navigate through complex microenvironments. The results of this study unraveled a role for the microtubule cytoskeleton in promoting the decision making process during path finding and for the first time point towards a microtubule-mediated function in cell shape maintenance of highly ramified cells such as dendritic cells. Furthermore, we found that migrating low-adhesive leukocytes are able to instantaneously adapt to increased tensile load by engaging adhesion receptors. This response was only occurring tangential to the substrate while adhesive properties in the vertical direction were not increased. As leukocytes are primed for rapid migration velocities, these results demonstrate that leukocyte integrins are able to confer a high level of traction forces parallel to the cell membrane along the direction of migration without wasting energy in gluing the cell to the substrate. Thus, the data in the here presented thesis provide new insights into the pivotal role of cytoskeletal dynamics and the mechanisms of force transduction during leukocyte migration. Thereby the here presented results help to further define fundamental principles underlying leukocyte migration and open up potential therapeutic avenues of clinical relevance. }, author = {Kopf, Aglaja}, isbn = {978-3-99078-002-2}, issn = {2663-337X}, keywords = {cell biology, immunology, leukocyte, migration, microfluidics}, pages = {171}, publisher = {Institute of Science and Technology Austria}, title = {{The implication of cytoskeletal dynamics on leukocyte migration}}, doi = {10.15479/AT:ISTA:6891}, year = {2019}, } @article{8440, abstract = {Mycobacterium tuberculosis can remain dormant in the host, an ability that explains the failure of many current tuberculosis treatments. Recently, the natural products cyclomarin, ecumicin, and lassomycin have been shown to efficiently kill Mycobacterium tuberculosis persisters. Their target is the N-terminal domain of the hexameric AAA+ ATPase ClpC1, which recognizes, unfolds, and translocates protein substrates, such as proteins containing phosphorylated arginine residues, to the ClpP1P2 protease for degradation. Surprisingly, these antibiotics do not inhibit ClpC1 ATPase activity, and how they cause cell death is still unclear. Here, using NMR and small-angle X-ray scattering, we demonstrate that arginine-phosphate binding to the ClpC1 N-terminal domain induces millisecond dynamics. We show that these dynamics are caused by conformational changes and do not result from unfolding or oligomerization of this domain. Cyclomarin binding to this domain specifically blocked these N-terminal dynamics. On the basis of these results, we propose a mechanism of action involving cyclomarin-induced restriction of ClpC1 dynamics, which modulates the chaperone enzymatic activity leading eventually to cell death.}, author = {Weinhäupl, Katharina and Brennich, Martha and Kazmaier, Uli and Lelievre, Joel and Ballell, Lluis and Goldberg, Alfred and Schanda, Paul and Fraga, Hugo}, issn = {0021-9258}, journal = {Journal of Biological Chemistry}, keywords = {Cell Biology, Biochemistry, Molecular Biology}, number = {22}, pages = {8379--8393}, publisher = {American Society for Biochemistry & Molecular Biology}, title = {{The antibiotic cyclomarin blocks arginine-phosphate–induced millisecond dynamics in the N-terminal domain of ClpC1 from Mycobacterium tuberculosis}}, doi = {10.1074/jbc.ra118.002251}, volume = {293}, year = {2018}, } @article{6354, abstract = {Blood platelets are critical for hemostasis and thrombosis, but also play diverse roles during immune responses. We have recently reported that platelets migrate at sites of infection in vitro and in vivo. Importantly, platelets use their ability to migrate to collect and bundle fibrin (ogen)-bound bacteria accomplishing efficient intravascular bacterial trapping. Here, we describe a method that allows analyzing platelet migration in vitro, focusing on their ability to collect bacteria and trap bacteria under flow.}, author = {Fan, Shuxia and Lorenz, Michael and Massberg, Steffen and Gärtner, Florian R}, issn = {2331-8325}, journal = {Bio-Protocol}, keywords = {Platelets, Cell migration, Bacteria, Shear flow, Fibrinogen, E. coli}, number = {18}, publisher = {Bio-Protocol}, title = {{Platelet migration and bacterial trapping assay under flow}}, doi = {10.21769/bioprotoc.3018}, volume = {8}, year = {2018}, } @article{15155, abstract = {The C-terminal transactivation domain (TAD) of BMAL1 (brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and, consequently, contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Toward this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination.}, author = {Gustafson, Chelsea L. and Parsley, Nicole C. and Asimgil, Hande and Lee, Hsiau-Wei and Ahlbach, Christopher and Michael, Alicia Kathleen and Xu, Haiyan and Williams, Owen L. and Davis, Tara L. and Liu, Andrew C. and Partch, Carrie L.}, issn = {1097-2765}, journal = {Molecular Cell}, keywords = {Cell Biology, Molecular Biology}, number = {4}, pages = {447--457.e7}, publisher = {Elsevier}, title = {{A slow conformational switch in the BMAL1 transactivation domain modulates circadian rhythms}}, doi = {10.1016/j.molcel.2017.04.011}, volume = {66}, year = {2017}, } @article{11067, abstract = {Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate.}, author = {Toda, Tomohisa and Hsu, Jonathan Y. and Linker, Sara B. and Hu, Lauren and Schafer, Simon T. and Mertens, Jerome and Jacinto, Filipe V. and HETZER, Martin W and Gage, Fred H.}, issn = {1934-5909}, journal = {Cell Stem Cell}, keywords = {Cell Biology, Genetics, Molecular Medicine}, number = {5}, pages = {618--634.e7}, publisher = {Elsevier}, title = {{Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells}}, doi = {10.1016/j.stem.2017.08.012}, volume = {21}, year = {2017}, } @misc{5560, abstract = {This repository contains the data collected for the manuscript "Biased partitioning of the multi-drug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity". The data is compressed into a single archive. Within the archive, different folders correspond to figures of the main text and the SI of the related publication. Data is saved as plain text, with each folder containing a separate readme file describing the format. Typically, the data is from fluorescence microscopy measurements of single cells growing in a microfluidic "mother machine" device, and consists of relevant values (primarily arbitrary unit or normalized fluorescence measurements, and division times / growth rates) after raw microscopy images have been processed, segmented, and their features extracted, as described in the methods section of the related publication.}, author = {Bergmiller, Tobias and Andersson, Anna M and Tomasek, Kathrin and Balleza, Enrique and Kiviet, Daniel and Hauschild, Robert and Tkacik, Gasper and Guet, Calin C}, keywords = {single cell microscopy, mother machine microfluidic device, AcrAB-TolC pump, multi-drug efflux, Escherichia coli}, publisher = {Institute of Science and Technology Austria}, title = {{Biased partitioning of the multi-drug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity}}, doi = {10.15479/AT:ISTA:53}, year = {2017}, } @misc{5570, abstract = {Matlab script to calculate the forward migration indexes (/) from TrackMate spot-statistics files.}, author = {Hauschild, Robert}, keywords = {Cell migration, tracking, forward migration index, FMI}, publisher = {Institute of Science and Technology Austria}, title = {{Forward migration indexes}}, doi = {10.15479/AT:ISTA:75}, year = {2017}, } @article{11069, abstract = {Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.}, author = {Hatch, Emily M. and HETZER, Martin W}, issn = {0021-9525}, journal = {Journal of Cell Biology}, keywords = {Cell Biology}, number = {1}, pages = {27--36}, publisher = {Rockefeller University Press}, title = {{Nuclear envelope rupture is induced by actin-based nucleus confinement}}, doi = {10.1083/jcb.201603053}, volume = {215}, year = {2016}, } @misc{5555, abstract = {This FIJI script calculates the population average of the migration speed as a function of time of all cells from wide field microscopy movies.}, author = {Hauschild, Robert}, keywords = {cell migration, wide field microscopy, FIJI}, publisher = {Institute of Science and Technology Austria}, title = {{Fiji script to determine average speed and direction of migration of cells}}, doi = {10.15479/AT:ISTA:44}, year = {2016}, } @article{12196, abstract = {SNC1 (SUPPRESSOR OF NPR1, CONSTITUTIVE 1) is one of a suite of intracellular Arabidopsis NOD-like receptor (NLR) proteins which, upon activation, result in the induction of defense responses. However, the molecular mechanisms underlying NLR activation and the subsequent provocation of immune responses are only partially characterized. To identify negative regulators of NLR-mediated immunity, a forward genetic screen was undertaken to search for enhancers of the dwarf, autoimmune gain-of-function snc1 mutant. To avoid lethality resulting from severe dwarfism, the screen was conducted using mos4 (modifier of snc1, 4) snc1 plants, which display wild-type-like morphology and resistance. M2 progeny were screened for mutant, snc1-enhancing (muse) mutants displaying a reversion to snc1-like phenotypes. The muse9 mos4 snc1 triple mutant was found to exhibit dwarf morphology, elevated expression of the pPR2-GUS defense marker reporter gene and enhanced resistance to the oomycete pathogen Hyaloperonospora arabidopsidis Noco2. Via map-based cloning and Illumina sequencing, it was determined that the muse9 mutation is in the gene encoding the SWI/SNF chromatin remodeler SYD (SPLAYED), and was thus renamed syd-10. The syd-10 single mutant has no observable alteration from wild-type-like resistance, although the syd-4 T-DNA insertion allele displays enhanced resistance to the bacterial pathogen Pseudomonas syringae pv. maculicola ES4326. Transcription of SNC1 is increased in both syd-4 and syd-10. These data suggest that SYD plays a subtle, specific role in the regulation of SNC1 expression and SNC1-mediated immunity. SYD may work with other proteins at the chromatin level to repress SNC1 transcription; such regulation is important for fine-tuning the expression of NLR-encoding genes to prevent unpropitious autoimmunity.}, author = {Johnson, Kaeli C.M. and Xia, Shitou and Feng, Xiaoqi and Li, Xin}, issn = {0032-0781}, journal = {Plant and Cell Physiology}, keywords = {Cell Biology, Plant Science, Physiology, General Medicine}, number = {8}, pages = {1616--1623}, publisher = {Oxford University Press}, title = {{The chromatin remodeler SPLAYED negatively regulates SNC1-mediated immunity}}, doi = {10.1093/pcp/pcv087}, volume = {56}, year = {2015}, } @article{15160, abstract = {The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms.}, author = {Michael, Alicia Kathleen and Harvey, Stacy L. and Sammons, Patrick J. and Anderson, Amanda P. and Kopalle, Hema M. and Banham, Alison H. and Partch, Carrie L.}, issn = {1097-2765}, journal = {Molecular Cell}, keywords = {Cell Biology, Molecular Biology}, number = {5}, pages = {743--754}, publisher = {Elsevier}, title = {{Cancer/Testis antigen PASD1 silences the circadian clock}}, doi = {10.1016/j.molcel.2015.03.031}, volume = {58}, year = {2015}, } @article{11075, abstract = {Previously, we identified the nucleoporin gp210/Nup210 as a critical regulator of muscle and neuronal differentiation, but how this nucleoporin exerts its function and whether it modulates nuclear pore complex (NPC) activity remain unknown. Here, we show that gp210/Nup210 mediates muscle cell differentiation in vitro via its conserved N-terminal domain that extends into the perinuclear space. Removal of the C-terminal domain, which partially mislocalizes gp210/Nup210 away from NPCs, efficiently rescues the differentiation defect caused by the knockdown of endogenous gp210/Nup210. Unexpectedly, a gp210/Nup210 mutant lacking the NPC-targeting transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. We demonstrate that the endoplasmic reticulum (ER) stress-specific caspase cascade is exacerbated during Nup210 depletion and that blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells. Our results suggest that the role of gp210/Nup210 in cell differentiation is mediated by its large luminal domain, which can act independently of NPC association and appears to play a pivotal role in the maintenance of nuclear envelope/ER homeostasis.}, author = {Gomez-Cavazos, J. Sebastian and HETZER, Martin W}, issn = {1540-8140}, journal = {Journal of Cell Biology}, keywords = {Cell Biology}, number = {6}, pages = {671--681}, publisher = {Rockefeller University Press}, title = {{The nucleoporin gp210/Nup210 controls muscle differentiation by regulating nuclear envelope/ER homeostasis}}, doi = {10.1083/jcb.201410047}, volume = {208}, year = {2015}, } @article{11078, abstract = {Aging is associated with the decline of protein, cell, and organ function. Here, we use an integrated approach to characterize gene expression, bulk translation, and cell biology in the brains and livers of young and old rats. We identify 468 differences in protein abundance between young and old animals. The majority are a consequence of altered translation output, that is, the combined effect of changes in transcript abundance and translation efficiency. In addition, we identify 130 proteins whose overall abundance remains unchanged but whose sub-cellular localization, phosphorylation state, or splice-form varies. While some protein-level differences appear to be a generic property of the rats’ chronological age, the majority are specific to one organ. These may be a consequence of the organ’s physiology or the chronological age of the cells within the tissue. Taken together, our study provides an initial view of the proteome at the molecular, sub-cellular, and organ level in young and old rats.}, author = {Ori, Alessandro and Toyama, Brandon H. and Harris, Michael S. and Bock, Thomas and Iskar, Murat and Bork, Peer and Ingolia, Nicholas T. and HETZER, Martin W and Beck, Martin}, issn = {2405-4712}, journal = {Cell Systems}, keywords = {Cell Biology, Histology, Pathology and Forensic Medicine}, number = {3}, pages = {P224--237}, publisher = {Elsevier}, title = {{Integrated transcriptome and proteome analyses reveal organ-specific proteome deterioration in old rats}}, doi = {10.1016/j.cels.2015.08.012}, volume = {1}, year = {2015}, } @article{11079, abstract = {Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging.}, author = {Mertens, Jerome and Paquola, Apuã C.M. and Ku, Manching and Hatch, Emily and Böhnke, Lena and Ladjevardi, Shauheen and McGrath, Sean and Campbell, Benjamin and Lee, Hyungjun and Herdy, Joseph R. and Gonçalves, J. Tiago and Toda, Tomohisa and Kim, Yongsung and Winkler, Jürgen and Yao, Jun and HETZER, Martin W and Gage, Fred H.}, issn = {1934-5909}, journal = {Cell Stem Cell}, keywords = {Cell Biology, Genetics, Molecular Medicine}, number = {6}, pages = {705--718}, publisher = {Elsevier}, title = {{Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects}}, doi = {10.1016/j.stem.2015.09.001}, volume = {17}, year = {2015}, } @article{11081, abstract = {In eukaryotic cells the nuclear genome is enclosed by the nuclear envelope (NE). In metazoans, the NE breaks down in mitosis and it has been assumed that the physical barrier separating nucleoplasm and cytoplasm remains intact during the rest of the cell cycle and cell differentiation. However, recent studies suggest that nonmitotic NE remodeling plays a critical role in development, virus infection, laminopathies, and cancer. Although the mechanisms underlying these NE restructuring events are currently being defined, one common theme is activation of protein kinase C family members in the interphase nucleus to disrupt the nuclear lamina, demonstrating the importance of the lamina in maintaining nuclear integrity.}, author = {Hatch, Emily and HETZER, Martin W}, issn = {1540-8140}, journal = {Journal of Cell Biology}, keywords = {Cell Biology}, number = {2}, pages = {133--141}, publisher = {Rockefeller University Press}, title = {{Breaching the nuclear envelope in development and disease}}, doi = {10.1083/jcb.201402003}, volume = {205}, year = {2014}, } @article{11082, abstract = {The nuclear pore complex (NPC) plays a critical role in gene expression by mediating import of transcription regulators into the nucleus and export of RNA transcripts to the cytoplasm. Emerging evidence suggests that in addition to mediating transport, a subset of nucleoporins (Nups) engage in transcriptional activation and elongation at genomic loci that are not associated with NPCs. The underlying mechanism and regulation of Nup mobility on and off nuclear pores remain unclear. Here we show that Nup50 is a mobile Nup with a pronounced presence both at the NPC and in the nucleoplasm that can move between these different localizations. Strikingly, the dynamic behavior of Nup50 in both locations is dependent on active transcription by RNA polymerase II and requires the N-terminal half of the protein, which contains importin α– and Nup153-binding domains. However, Nup50 dynamics are independent of importin α, Nup153, and Nup98, even though the latter two proteins also exhibit transcription-dependent mobility. Of interest, depletion of Nup50 from C2C12 myoblasts does not affect cell proliferation but inhibits differentiation into myotubes. Taken together, our results suggest a transport-independent role for Nup50 in chromatin biology that occurs away from the NPC.}, author = {Buchwalter, Abigail L. and Liang, Yun and HETZER, Martin W}, issn = {1059-1524}, journal = {Molecular Biology of the Cell}, keywords = {Cell Biology, Molecular Biology}, number = {16}, pages = {2472--2484}, publisher = {American Society for Cell Biology}, title = {{Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics}}, doi = {10.1091/mbc.e14-04-0865}, volume = {25}, year = {2014}, } @article{11083, abstract = {Nuclear pore complex (NPC) proteins are known for their critical roles in regulating nucleocytoplasmic traffic of macromolecules across the nuclear envelope. However, recent findings suggest that some nucleoporins (Nups), including Nup98, have additional functions in developmental gene regulation. Nup98, which exhibits transcription-dependent mobility at the NPC but can also bind chromatin away from the nuclear envelope, is frequently involved in chromosomal translocations in a subset of patients suffering from acute myeloid leukemia (AML). A common paradigm suggests that Nup98 translocations cause aberrant transcription when they are recuited to aberrant genomic loci. Importantly, this model fails to account for the potential loss of wild type (WT) Nup98 function in the presence of Nup98 translocation mutants. Here we examine how the cell might regulate Nup98 nucleoplasmic protein levels to control transcription in healthy cells. In addition, we discuss the possibility that dominant negative Nup98 fusion proteins disrupt the transcriptional activity of WT Nup98 in the nucleoplasm to drive AML.}, author = {Franks, Tobias M. and HETZER, Martin W}, issn = {0962-8924}, journal = {Trends in Cell Biology}, keywords = {Cell Biology}, number = {3}, pages = {112--117}, publisher = {Elsevier}, title = {{The role of Nup98 in transcription regulation in healthy and diseased cells}}, doi = {10.1016/j.tcb.2012.10.013}, volume = {23}, year = {2013}, } @article{11084, abstract = {Protein turnover is an effective way of maintaining a functional proteome, as old and potentially damaged polypeptides are destroyed and replaced by newly synthesized copies. An increasing number of intracellular proteins, however, have been identified that evade this turnover process and instead are maintained over a cell's lifetime. This diverse group of long-lived proteins might be particularly prone to accumulation of damage and thus have a crucial role in the functional deterioration of key regulatory processes during ageing.}, author = {Toyama, Brandon H. and HETZER, Martin W}, issn = {1471-0072}, journal = {Nature Reviews Molecular Cell Biology}, keywords = {Cell Biology, Molecular Biology}, pages = {55--61}, publisher = {Springer Nature}, title = {{Protein homeostasis: Live long, won't prosper}}, doi = {10.1038/nrm3496}, volume = {14}, year = {2013}, } @article{11089, abstract = {The Nuclear Envelope (NE) contains over 100 different proteins that associate with nuclear components such as chromatin, the lamina and the transcription machinery. Mutations in genes encoding NE proteins have been shown to result in tissue-specific defects and disease, suggesting cell-type specific differences in NE composition and function. Consistent with these observations, recent studies have revealed unexpected functions for numerous NE associated proteins during cell differentiation and development. Here we review the latest insights into the roles played by the NE in cell differentiation, development, disease and aging, focusing primarily on inner nuclear membrane (INM) proteins and nuclear pore components.}, author = {Gomez-Cavazos, J Sebastian and HETZER, Martin W}, issn = {0955-0674}, journal = {Current Opinion in Cell Biology}, keywords = {Cell Biology}, number = {6}, pages = {775--783}, publisher = {Elsevier}, title = {{Outfits for different occasions: tissue-specific roles of Nuclear Envelope proteins}}, doi = {10.1016/j.ceb.2012.08.008}, volume = {24}, year = {2012}, } @article{11091, abstract = {Neoplastic cells are often characterized by specific morphological abnormalities of the nuclear envelope (NE), which have been used for cancer diagnosis for more than a century. The NE is a double phospholipid bilayer that encapsulates the nuclear genome, regulates all nuclear trafficking of RNAs and proteins and prevents the passive diffusion of macromolecules between the nucleoplasm and the cytoplasm. Whether there is a consequence to the proper functioning of the cell and loss of structural integrity of the nucleus remains unclear. Using live cell imaging, we characterize a phenomenon wherein nuclei of several proliferating human cancer cell lines become temporarily ruptured during interphase. Strikingly, NE rupturing was associated with the mislocalization of nucleoplasmic and cytoplasmic proteins and, in the most extreme cases, the entrapment of cytoplasmic organelles in the nuclear interior. In addition, we observed the formation of micronuclei-like structures during interphase and the movement of chromatin out of the nuclear space. The frequency of these NE rupturing events was higher in cells in which the nuclear lamina, a network of intermediate filaments providing mechanical support to the NE, was not properly formed. Our data uncover the existence of a NE instability that has the potential to change the genomic landscape of cancer cells.}, author = {Vargas, Jesse D. and Hatch, Emily M. and Anderson, Daniel J. and HETZER, Martin W}, issn = {1949-1042}, journal = {Nucleus}, keywords = {Cell Biology}, number = {1}, pages = {88--100}, publisher = {Taylor & Francis}, title = {{Transient nuclear envelope rupturing during interphase in human cancer cells}}, doi = {10.4161/nucl.18954}, volume = {3}, year = {2012}, }