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Nature Cell Biology

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https://www.readbyqxmd.com/read/27918550/selective-y-centromere-inactivation-triggers-chromosome-shattering-in-micronuclei-and-repair-by-non-homologous-end-joining
#1
Peter Ly, Levi S Teitz, Dong H Kim, Ofer Shoshani, Helen Skaletsky, Daniele Fachinetti, David C Page, Don W Cleveland
Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements known as chromothripsis, but the underlying mechanisms remain unresolved. Here we developed an inducible Y centromere-selective inactivation strategy by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells. Using this approach, we identified a temporal cascade of events that are initiated following centromere inactivation involving chromosome missegregation, fragmentation, and re-ligation that span three consecutive cell cycles...
December 5, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27918549/a-hypoxia-responsive-traf6-atm-h2ax-signalling-axis-promotes-hif1%C3%AE-activation-tumorigenesis-and%C3%A2-metastasis
#2
Abdol-Hossein Rezaeian, Chien-Feng Li, Ching-Yuan Wu, Xian Zhang, Jorge Delacerda, M James You, Fei Han, Zhen Cai, Yun Seong Jeong, Guoxiang Jin, Liem Phan, Ping-Chieh Chou, Mong-Hong Lee, Mien-Chie Hung, Dos Sarbassov, Hui-Kuan Lin
The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis...
December 5, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27870831/asymmetric-division-coordinates-collective-cell-migration-in-angiogenesis
#3
Guilherme Costa, Kyle I Harrington, Holly E Lovegrove, Donna J Page, Shilpa Chakravartula, Katie Bentley, Shane P Herbert
The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis...
November 21, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27870830/clonal-fate-mapping-quantifies-the-number-of%C3%A2-haematopoietic-stem-cells-that-arise-during%C3%A2-development
#4
Jonathan Henninger, Buyung Santoso, Stefan Hans, Ellen Durand, Jessica Moore, Christian Mosimann, Michael Brand, David Traver, Leonard Zon
Haematopoietic stem cells (HSCs) arise in the developing aorta during embryogenesis. The number of HSC clones born has been estimated through transplantation, but experimental approaches to assess the absolute number of forming HSCs in a native setting have remained challenging. Here, we applied single-cell and clonal analysis of HSCs in zebrafish to quantify developing HSCs. Targeting creER(T2) in developing cd41:eGFP(+) HSCs enabled long-term assessment of their blood contribution. We also applied the Brainbow-based multicolour Zebrabow system with drl:creER(T2) that is active in early haematopoiesis to induce heritable colour barcoding unique to each HSC and its progeny...
November 21, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27870828/agonist-stimulated-phosphatidylinositol-3-4-5-trisphosphate-generation-by-scaffolded-phosphoinositide-kinases
#5
Suyong Choi, Andrew C Hedman, Samar Sayedyahossein, Narendra Thapa, David B Sacks, Richard A Anderson
Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) is crucial for development, cell growth and survival, and motility, and it becomes dysfunctional in many diseases including cancers. Here we reveal a mechanism for PtdIns(3,4,5)P3 generation by scaffolded phosphoinositide kinases. In this pathway, class I phosphatidylinositol-3-OH kinase (PI(3)K) is assembled by IQGAP1 with PI(4)KIIIα and PIPKIα, which sequentially generate PtdIns(3,4,5)P3 from phosphatidylinositol...
November 21, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27842057/engulfed-cadherin-fingers-are-polarized-junctional-structures-between-collectively-migrating-endothelial%C3%A2-cells
#6
Arnold Hayer, Lin Shao, Mingyu Chung, Lydia-Marie Joubert, Hee Won Yang, Feng-Chiao Tsai, Anjali Bisaria, Eric Betzig, Tobias Meyer
The development and maintenance of tissues requires collective cell movement, during which neighbouring cells coordinate the polarity of their migration machineries. Here, we ask how polarity signals are transmitted from one cell to another across symmetrical cadherin junctions, during collective migration. We demonstrate that collectively migrating endothelial cells have polarized VE-cadherin-rich membrane protrusions, 'cadherin fingers', which leading cells extend from their rear and follower cells engulf at their front, thereby generating opposite membrane curvatures and asymmetric recruitment of curvature-sensing proteins...
November 14, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27820601/scai-promotes-dna-double-strand-break-repair-in-distinct-chromosomal-contexts
#7
Rebecca Kring Hansen, Andreas Mund, Sara Lund Poulsen, Maria Sandoval, Karolin Klement, Katerina Tsouroula, Maxim A X Tollenaere, Markus Räschle, Rebeca Soria, Stefan Offermanns, Thomas Worzfeld, Robert Grosse, Dominique T Brandt, Björn Rozell, Matthias Mann, Francesca Cole, Evi Soutoglou, Aaron A Goodarzi, Jeremy A Daniel, Niels Mailand, Simon Bekker-Jensen
DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions, whose accurate repair by non-homologous end-joining (NHEJ) or homologous recombination (HR) is crucial for genome integrity and is strongly influenced by the local chromatin environment. Here, we identify SCAI (suppressor of cancer cell invasion) as a 53BP1-interacting chromatin-associated protein that promotes the functionality of several DSB repair pathways in mammalian cells. SCAI undergoes prominent enrichment at DSB sites through dual mechanisms involving 53BP1-dependent recruitment to DSB-surrounding chromatin and 53BP1-independent accumulation at resected DSBs...
November 7, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27820600/direct-reprogramming-of-fibroblasts-into-renal-tubular-epithelial-cells-by-defined-transcription-factors
#8
Michael M Kaminski, Jelena Tosic, Catena Kresbach, Hannes Engel, Jonas Klockenbusch, Anna-Lena Müller, Roman Pichler, Florian Grahammer, Oliver Kretz, Tobias B Huber, Gerd Walz, Sebastian J Arnold, Soeren S Lienkamp
Direct reprogramming by forced expression of transcription factors can convert one cell type into another. Thus, desired cell types can be generated bypassing pluripotency. However, direct reprogramming towards renal cells remains an unmet challenge. Here, we identify renal cell fate-inducing factors on the basis of their tissue specificity and evolutionarily conserved expression, and demonstrate that combined expression of Emx2, Hnf1b, Hnf4a and Pax8 converts mouse and human fibroblasts into induced renal tubular epithelial cells (iRECs)...
November 7, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27820599/tissue-mechanics-promote-idh1-dependent-hif1%C3%AE-tenascin-c-feedback-to-regulate-glioblastoma%C3%A2-aggression
#9
Yekaterina A Miroshnikova, Janna K Mouw, J Matthew Barnes, Michael W Pickup, Johnathan N Lakins, Youngmi Kim, Khadjia Lobo, Anders I Persson, Gerald F Reis, Tracy R McKnight, Eric C Holland, Joanna J Phillips, Valerie M Weaver
Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling...
November 7, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27798604/lgr6-labels-a-rare-population-of-mammary-gland-progenitor-cells-that-are-able-to-originate-luminal-mammary-tumours
#10
Leander Blaas, Fabio Pucci, Hendrik A Messal, Agneta B Andersson, E Josue Ruiz, Marco Gerling, Iyadh Douagi, Bradley Spencer-Dene, Alexandra Musch, Richard Mitter, Leena Bhaw, Richard Stone, Dorothee Bornhorst, Abdul K Sesay, Jos Jonkers, Gordon Stamp, Ilaria Malanchi, Rune Toftgård, Axel Behrens
The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem/progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are incompletely understood. Here we show that Lgr6 marks rare populations of cells in both basal and luminal mammary gland compartments in mice. Lineage tracing analysis showed that Lgr6(+) cells are unipotent progenitors, which expand clonally during puberty but diminish in adulthood. In pregnancy or following stimulation with ovarian hormones, adult Lgr6(+) cells regained proliferative potency and their progeny formed alveoli over repeated pregnancies...
October 31, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27775703/dnaja1-controls-the-fate-of-misfolded-mutant-p53-through-the-mevalonate-pathway
#11
Alejandro Parrales, Atul Ranjan, Swathi V Iyer, Subhash Padhye, Scott J Weir, Anuradha Roy, Tomoo Iwakuma
Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member...
October 24, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27775702/diversified-actin-protrusions-promote-environmental-exploration-but-are-dispensable-for-locomotion-of%C3%A2-leukocytes
#12
Alexander Leithner, Alexander Eichner, Jan Müller, Anne Reversat, Markus Brown, Jan Schwarz, Jack Merrin, David J J de Gorter, Florian Schur, Jonathan Bayerl, Ingrid de Vries, Stefan Wieser, Robert Hauschild, Frank P L Lai, Markus Moser, Dontscho Kerjaschki, Klemens Rottner, J Victor Small, Theresia E B Stradal, Michael Sixt
Most migrating cells extrude their front by the force of actin polymerization. Polymerization requires an initial nucleation step, which is mediated by factors establishing either parallel filaments in the case of filopodia or branched filaments that form the branched lamellipodial network. Branches are considered essential for regular cell motility and are initiated by the Arp2/3 complex, which in turn is activated by nucleation-promoting factors of the WASP and WAVE families. Here we employed rapid amoeboid crawling leukocytes and found that deletion of the WAVE complex eliminated actin branching and thus lamellipodia formation...
October 24, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27749822/snail1-dependent-p53-repression-regulates-expansion-and-activity-of-tumour-initiating-cells-in-breast-cancer
#13
Ting Ni, Xiao-Yan Li, Na Lu, Teng An, Zhi-Ping Liu, Rong Fu, Wen-Cong Lv, Yi-Wei Zhang, Xiao-Jun Xu, R Grant Rowe, Yong-Shun Lin, Amanda Scherer, Tamar Feinberg, Xiao-Qi Zheng, Bao-An Chen, X Shirley Liu, Qing-Long Guo, Zhao-Qiu Wu, Stephen J Weiss
The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development...
October 17, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27749820/the-actin-cable-is-dispensable-in-directing-dorsal-closure-dynamics-but-neutralizes-mechanical-stress-to-prevent-scarring-in-the-drosophila-embryo
#14
Antoine Ducuing, Stéphane Vincent
The actin cable is a supracellular structure that embryonic epithelia produce to close gaps. However, the action of the cable remains debated. Here, we address the function of the cable using Drosophila dorsal closure, a paradigm to understand wound healing. First, we show that the actin cytoskeleton protein Zasp52 is specifically required for actin cable formation. Next, we used Zasp52 loss of function to dissect the mechanism of action of the cable. Surprisingly, closure dynamics are perfect in Zasp52 mutants: the cable is therefore dispensable for closure, even in the absence of the amnioserosa...
October 17, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27723720/etaa1-acts-at-stalled-replication-forks-to-maintain-genome-integrity
#15
Thomas E Bass, Jessica W Luzwick, Gina Kavanaugh, Clinton Carroll, Huzefa Dungrawala, Gloria G Glick, Michael D Feldkamp, Reid Putney, Walter J Chazin, David Cortez
The ATR checkpoint kinase coordinates cellular responses to DNA replication stress. Budding yeast contain three activators of Mec1 (the ATR orthologue); however, only TOPBP1 is known to activate ATR in vertebrates. We identified ETAA1 as a replication stress response protein in two proteomic screens. ETAA1-deficient cells accumulate double-strand breaks, sister chromatid exchanges, and other hallmarks of genome instability. They are also hypersensitive to replication stress and have increased frequencies of replication fork collapse...
October 10, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27723719/mitotic-binding-of-esrrb-marks-key-regulatory-regions-of-the-pluripotency-network
#16
Nicola Festuccia, Agnès Dubois, Sandrine Vandormael-Pournin, Elena Gallego Tejeda, Adrien Mouren, Sylvain Bessonnard, Florian Mueller, Caroline Proux, Michel Cohen-Tannoudji, Pablo Navarro
Pluripotent mouse embryonic stem cells maintain their identity throughout virtually infinite cell divisions. This phenomenon, referred to as self-renewal, depends on a network of sequence-specific transcription factors (TFs) and requires daughter cells to accurately reproduce the gene expression pattern of the mother. However, dramatic chromosomal changes take place in mitosis, generally leading to the eviction of TFs from chromatin. Here, we report that Esrrb, a major pluripotency TF, remains bound to key regulatory regions during mitosis...
October 10, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27723718/progress-towards-generation-of-human-haematopoietic-stem-cells
#17
Lara Wahlster, George Q Daley
De novo generation of haematopoietic stem cells from different human pluripotent stem cell sources remains a high priority for haematology and regenerative medicine. At present, efficient derivation of functional haematopoietic stem cells with the capability for definitive in vivo engraftment and multi-lineage potential remains challenging. Here, we discuss recent progress and strategies to overcome obstacles that have thwarted past efforts. In addition, we review promising advances in the generation of mature blood lineages and the potential of induced pluripotent stem cells...
October 10, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27694890/an-interaction-between-scribble-and-the-nadph-oxidase-complex-controls-m1-macrophage-polarization-and-function
#18
Weiyue Zheng, Masataka Umitsu, Ishaan Jagan, Charles W Tran, Noboru Ishiyama, Michael BeGora, Kiyomi Araki, Pamela S Ohashi, Mitsuhiko Ikura, Senthil K Muthuswamy
The polarity protein Scribble (SCRIB) regulates apical-basal polarity, directional migration and tumour suppression in Drosophila and mammals. Here we report that SCRIB is an important regulator of myeloid cell functions including bacterial infection and inflammation. SCRIB interacts directly with the NADPH oxidase (NOX) complex in a PSD95/Dlg/ZO-1 (PDZ)-domain-dependent manner and is required for NOX-induced reactive oxygen species (ROS) generation in culture and in vivo. On bacterial infection, SCRIB localized to phagosomes in a leucine-rich repeat-dependent manner and promoted ROS production within phagosomes to kill bacteria...
October 3, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27642788/induction-of-lifr-confers-a-dormancy-phenotype-in-breast-cancer-cells-disseminated-to-the-bone-marrow
#19
Rachelle W Johnson, Elizabeth C Finger, Monica M Olcina, Marta Vilalta, Todd Aguilera, Yu Miao, Alyssa R Merkel, Joshua R Johnson, Julie A Sterling, Joy Y Wu, Amato J Giaccia
Breast cancer cells frequently home to the bone marrow, where they may enter a dormant state before forming a bone metastasis. Several members of the interleukin-6 (IL-6) cytokine family are implicated in breast cancer bone colonization, but the role for the IL-6 cytokine leukaemia inhibitory factor (LIF) in this process is unknown. We tested the hypothesis that LIF provides a pro-dormancy signal to breast cancer cells in the bone. In breast cancer patients, LIF receptor (LIFR) levels are lower with bone metastases and are significantly and inversely correlated with patient outcome and hypoxia gene activity...
September 19, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27897157/getting-a-grip-on-collective-cell-migration
#20
Tamal Das, Joachim P Spatz
Many cell types in our body move in a collective manner, which requires individual cells to align their movements relative to that of their neighbours. A mechanism is now described in which cadherin-rich protrusions are extended from leading migrating cells and engulfed by follower cells to guide collective migration.
December 2016: Nature Cell Biology
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