archive-com.com » COM » C » CELL-RESEARCH.COM

Total: 1754

Choose link from "Titles, links and description words view":

Or switch to "Titles and links view".
  • Cell Research
    Dsnx3 mutant clones in wing discs Wg levels in the culture medium of Dsnx3 depleted S2 cells are also markedly reduced Importantly Wls levels are strikingly reduced in Dsnx3 mutant cells and overexpression of Wls can rescue the Wg secretion defect observed in Dsnx3 mutant cells Moreover DSNX3 can interact with the retromer component Vps35 and co localize with Vps35 in early endosomes These data indicate that DSNX3 regulates Wg secretion via retromer dependent Wls recycling In contrast we found that Wg secretion is not defective in cells mutant for Drosophila snx1 and snx6 two components of the classical retromer complex Ectopic expression of DSNX1 or DSNX6 fails to rescue the Wg secretion defect in Dsnx3 mutant wing discs and in Dsnx3 dsRNA treated S2 cells These data demonstrate the specificity of the DSNX3 retromer complex in Wls recycling Together our findings suggest that DSNX3 acts as a cargo specific component of retromer which is required for endocytic recycling of Wls and Wg Wnt secretion An atypical component of RNA directed DNA methylation machinery has both DNA methylation dependent and independent roles in locus specific transcriptional gene silencing Jun Liu 1 Ge Bai 2 3 Cuijun Zhang 1 Wei Chen 2 Jinxing Zhou 1 Suwei Zhang 1 Qing Chen 1 Xin Deng 2 4 Xin Jian He 1 and Jian Kang Zhu 2 DTF1 siRNA DNA methylation transcriptional gene silencing RdDM Full Text PDF RNA directed DNA methylation RdDM is an important de novo DNA methylation pathway in plants RdDM mediates the transcriptional silencing of many endogenous genomic loci most of which are transposon related A forward genetics screen identified DTF1 DNA binding transcription factor 1 as a new component for RdDM in Arabidopsis Loss of function mutations in DTF1 release the transcriptional silencing of RdDM target loci and reduce the accumulation of 24 nt small interfering RNAs siRNAs from some of the targets Interestingly in the dtf1 mutant plants the release of transcriptional gene silencing at solo LTR is accompanied by decreased siRNA accumulation but not by reduced DNA methylation These results suggest that DTF1 is an atypical component of RdDM and has both DNA methylation dependent and independent roles in transcriptional gene silencing We suggest that besides DNA methylation siRNAs may cause some other uncharacterized epigenetic modifications that lead to transcriptional gene silencing Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells Xiaomin Wen Haifeng Liu Gang Xiao and Xiaolong Liu Cell Research 2011 21 1701 1710 doi 10 1038 cr 2011 183 published online 22 November 2011 Full Text PDF The roles of the reprogramming factors Oct4 Sox2 c Myc and Klf4 in early T cell development are incompletely defined Here we show that Klf4 is the only reprogramming factor whose expression is downregulated when early thymic progenitors ETPs differentiate into T cells Enforced expression of Klf4 in uncommitted progenitors severely impaired T cell development mainly at the DN2 to DN3 transition when T cell lineage commitment occurs and affected the

    Original URL path: http://www.cell-research.com/artsmore.asp?id=19 (2016-02-14)
    Open archived version from archive


  • Cell Research
    1 Lingyun Zhu 1 2 Yujing Zhang 1 Jing Li 1 Zhen Bian 1 Xiangying Liang 1 Xing Cai 1 Y Cell Research 2012 22 107 126 doi 10 1038 cr 2011 158 published online 20 September 2011 Full Text PDF Caspase cleavage of cytochrome c1 disrupts mitochondrial function and enhances cytochrome c release Yushan Zhu 1 2 Min Li 3 Xiaohui Wang 1 Haijing Jin 1 Shusen Liu1 1 Jianxin Xu 3 and Quan Chen 1 2 Cell Research 2012 22 127 141 doi 10 1038 cr 2011 82 published online 17 May 2011 Full Text PDF Mitochondrial catastrophe can be the cause or consequence of apoptosis and is associated with a number of pathophysiological conditions The exact relationship between mitochondrial catastrophe and caspase activation is not completely understood Here we addressed the underlying mechanism explaining how activated caspase could feedback to attack mitochondria to amplify further cytochrome c cyto c release We discovered that cytochrome c1 cyto c1 in the bc1 complex of the mitochondrial respiration chain was a novel substrate of caspase 3 casp 3 We found that cyto c1 was cleaved at the site of D106 which is critical for binding with cyto c following apoptotic stresses or targeted expression of casp 3 into the mitochondrial intermembrane space We demonstrated that this cleavage was closely linked with further cyto c release and mitochondrial catastrophe These mitochondrial events could be effectively blocked by expressing non cleavable cyto c1 D106A or by caspase inhibitor z VAD fmk Our results demonstrate that the cleavage of cyto c1 represents a critical step for the feedback amplification of cyto c release by caspases and subsequent mitochondrial catastrophe Highly efficient derivation of ventricular cardiomyocytes from induced pluripotent stem cells with a distinct epigenetic signature Huansheng Xu 1 2 3 B Alexander Yi 1 2 3 Hao Wu 1 2 3 Christoph Bock 2 3 4 Hongcang Gu 2 3 4 Kathy O Lui 1 2 3 Joo Hye C Park 1 Ying Shao 1 Alyssa K Riley Cell Research 2012 22 142 154 doi 10 1038 cr 2011 171 published online 8 November 2011 Full Text PDF Cardiomyocytes derived from pluripotent stem cells can be applied in drug testing disease modeling and cell based therapy However without procardiogenic growth factors the efficiency of cardiomyogenesis from pluripotent stem cells is usually low and the resulting cardiomyocyte population is heterogeneous Here we demonstrate that induced pluripotent stem cells iPSCs can be derived from murine ventricular myocytes VMs and consistent with other reports of iPSCs derived from various somatic cell types VM derived iPSCs ViPSCs exhibit a markedly higher propensity to spontaneously differentiate into beating cardiomyocytes as compared to genetically matched embryonic stem cells ESCs or iPSCs derived from tail tip fibroblasts Strikingly the majority of ViPSC derived cardiomyocytes display a ventricular phenotype The enhanced ventricular myogenesis in ViPSCs is mediated via increased numbers of cardiovascular progenitors at early stages of differentiation In order to investigate the mechanism of enhanced ventricular myogenesis from ViPSCs we performed global gene expression and DNA methylation analysis which revealed a distinct epigenetic signature that may be involved in specifying the VM fate in pluripotent stem cells Oct4 links multiple epigenetic pathways to the pluripotency network Junjun Ding 1 Huilei Xu 2 Francesco Faiola 1 Avi Ma ayan 2 and Jianlong Wang 1 Cell Research 2012 22 155 167 doi 10 1038 cr 2011 179 published online 15 November 2011 Oct4 is a well known transcription factor that plays fundamental roles in stem cell self renewal pluripotency and somatic cell reprogramming However limited information is available on Oct4 associated protein complexes and their intrinsic protein protein interactions that dictate Oct4 s critical regulatory activities Here we employed an improved affinity purification approach combined with mass spectrometry to purify Oct4 protein complexes in mouse embryonic stem cells mESCs and discovered many novel Oct4 partners important for self renewal and pluripotency of mESCs Notably we found that Oct4 is associated with multiple chromatin modifying complexes with documented as well as newly proved functional significance in stem cell maintenance and somatic cell reprogramming Our study establishes a solid biochemical basis for genetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploring alternative factor based reprogramming strategies The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming Athanasia D Panopoulos 1 Oscar Yanes 2 3 Sergio Ruiz 1 Yasuyuki S Kida1 Dinh Diep 4 Ralf Tautenhahn 2 Aída Herrerías 5 Erika M Batchelder 1 Nongluk Plon Cell Research 2012 22 168 177 doi 10 1038 cr 2011 177 published online 8 November 2011 Full Text PDF Metabolism is vital to every aspect of cell function yet the metabolome of induced pluripotent stem cells iPSCs remains largely unexplored Here we report using an untargeted metabolomics approach that human iPSCs share a pluripotent metabolomic signature with embryonic stem cells ESCs that is distinct from their parental cells and that is characterized by changes in metabolites involved in cellular respiration Examination of cellular bioenergetics corroborated with our metabolomic analysis and demonstrated that somatic cells convert from an oxidative state to a glycolytic state in pluripotency Interestingly the bioenergetics of various somatic cells correlated with their reprogramming efficiencies We further identified metabolites that differ between iPSCs and ESCs which revealed novel metabolic pathways that play a critical role in regulating somatic cell reprogramming Our findings are the first to globally analyze the metabolome of iPSCs and provide mechanistic insight into a new layer of regulation involved in inducing pluripotency and in evaluating iPSC and ESC equivalence Defining the nature of human pluripotent stem cell progeny Michaela Patterson 1 3 David N Chan 1 3 Iris Ha 1 Dana Case 4 Yongyan Cui 1 Ben Van Handel 1 3 Hanna KA Mikkola 1 2 3 4 and William E Lowry 1 2 3 4 Cell Research 2012 22 178 193 doi 10 1038 cr 2011 133 published online 16 August 2011 Full Text PDF While it is clear that human

    Original URL path: http://www.cell-research.com/artsmore.asp?id=18 (2016-02-14)
    Open archived version from archive

  • Cell Research
    reported previously that SNX10 is a unique member of the SNX family genes in that it has vacuolation activity in cells We investigate the biological function of SNX10 by loss of function assay in this study and demonstrate that SNX10 is required for the formation of primary cilia in cultured cells In zebrafish SNX10 is involved in ciliogenesis in the Kupffer s vesicle and essential for left right patterning of visceral organs Mechanistically SNX10 interacts with V ATPase complex and targets it to the centrosome where ciliogenesis is initiated Like SNX10 V ATPase regulates ciliogenesis in vitro and in vivo and does so synergistically with SNX10 We further discover that SNX10 and V ATPase regulate the ciliary trafficking of Rab8a which is a critical regulator of ciliary membrane extension These results identify an SNX10 V ATPase regulated vesicular trafficking pathway that is crucial for ciliogenesis and reveal that SNX10 V ATPase through the regulation of cilia formation in various organs play an essential role during early embryonic development The p97 ATPase associates with EEA1 to regulate the size of early endosomes Harish N Ramanathan and Yihong Ye Cell Research 2012 22 346 359 doi 10 1038 cr 2011 80 published online 10 May 2011 Full Text PDF The AAA ATPase associated with various cellular activities ATPase p97 acts on diverse substrate proteins to partake in various cellular processes such as membrane fusion and endoplasmic reticulum associated degradation ERAD In membrane fusion p97 is thought to function in analogy to the related ATPase NSF N ethylmaleimide sensitive fusion protein which promotes membrane fusion by disassembling a SNARE complex In ERAD p97 dislocates misfolded proteins from the ER membrane to facilitate their turnover by the proteasome Here we identify a novel function of p97 in endocytic trafficking by establishing the early endosomal autoantigen 1 EEA1 as a new p97 substrate We demonstrate that a fraction of p97 is localized to the early endosome membrane where it binds EEA1 via the N terminal C2H2 zinc finger domain Inhibition of p97 either by siRNA or a pharmacological inhibitor results in clustering and enlargement of early endosomes which is associated with an altered trafficking pattern for an endocytic cargo Mechanistically we show that p97 inhibition causes increased EEA1 self association at the endosome membrane We propose that p97 may regulate the size of early endosomes by governing the oligomeric state of EEA1 Cleavage of serum response factor mediated by enteroviral protease 2A contributes to impaired cardiac function Jerry Wong 1 Jingchun Zhang 1 Bobby Yanagawa 1 Zongshu Luo 1 Xiangsheng Yang 2 Jiang Chang 2 Bruce McManus 1 and Honglin Luo 1 Cell Research 2012 22 360 371 doi 10 1038 cr 2011 114 published online 19 July 2011 Full Text PDF Enteroviral infection can lead to dilated cardiomyopathy DCM which is a major cause of cardiovascular mortality worldwide However the pathogenetic mechanisms have not been fully elucidated Serum response factor SRF is a cardiac enriched transcription regulator controlling the expression of a variety of target genes including those involved in the contractile apparatus and immediate early response as well as microRNAs that silence the expression of cardiac regulatory factors Knockout of SRF in the heart results in downregulation of cardiac contractile gene expression and development of DCM The goal of this study is to understand the role of SRF in enterovirus induced cardiac dysfunction and progression to DCM Here we report that SRF is cleaved following enteroviral infection of mouse heart and cultured cardiomyocytes This cleavage is accompanied by impaired cardiac function and downregulation of cardiac specific contractile and regulatory genes Further investigation by antibody epitope mapping and site directed mutagenesis demonstrates that SRF cleavage occurs at the region of its transactivation domain through the action of virus encoded protease 2A Moreover we demonstrate that cleavage of SRF dissociates its transactivation domain from DNA binding domain resulting in the disruption of SRF mediated gene transactivation In addition to loss of functional SRF finally we report that the N terminal fragment of SRF cleavage products can also act as a dominant negative transcription factor which likely competes with the native SRF for DNA binding Our results suggest a mechanism by which virus infection impairs heart function and may offer a new therapeutic strategy to ameliorate myocardial damage and progression to DCM Structural basis for the recognition of Asef by adenomatous polyposis coli Zhenyi Zhang 1 2 Leyi Chen 1 2 Lei Gao 1 2 Kui Lin 1 2 Liang Zhu 1 2 4 Yang Lu 1 Xiaoshan Shi 1 3 Yuan Gao 1 2 Jing Zhou 1 2 Ping Xu 1 Cell Research 2012 22 372 386 doi 10 1038 cr 2011 119 published online 26 July 2011 Full Text PDF Adenomatous polyposis coli APC regulates cell cell adhesion and cell migration through activating the APC stimulated guanine nucleotide exchange factor GEF Asef which is usually autoinhibited through the binding between its Src homology 3 SH3 and Dbl homology DH domains The APC activated Asef stimulates the small GTPase Cdc42 which leads to decreased cell cell adherence and enhanced cell migration In colorectal cancers truncated APC constitutively activates Asef and promotes cancer cell migration and angiogenesis Here we report crystal structures of the human APC Asef complex We find that the armadillo repeat domain of APC uses a highly conserved surface groove to recognize the APC binding region ABR of Asef conformation of which changes dramatically upon binding to APC Key residues on APC and Asef for the complex formation were mutated and their importance was demonstrated by binding and activity assays Structural superimposition of the APC Asef complex with autoinhibited Asef suggests that the binding between APC and Asef might create a steric clash between Asef DH domain and APC which possibly leads to a conformational change in Asef that stimulates its GEF activity Our structures thus elucidate the molecular mechanism of Asef recognition by APC as well as provide a potential target for pharmaceutical intervention against cancers Serum inducible kinase is a positive

    Original URL path: http://www.cell-research.com/artsmore.asp?id=17 (2016-02-14)
    Open archived version from archive

  • Cell Research
    regions and are associated with various histone modifications and polymerase II binding The promoters with interacting enhancers are expressed at higher levels than those without interacting enhancers and their expression levels are positively correlated with the number of interacting enhancers Interestingly interacting promoters are co expressed in a tissue specific manner We also find that chromosomes are organized into multiple levels of interacting domains Our results define a global view of EP interactions and provide a data set to further understand mechanisms of enhancer targeting and long range chromatin organization The Gene Expression Omnibus accession number for the raw and analyzed chromatin interaction data is GSE32677 Mouse miRNA 709 directly regulates miRNA 15a 16 1 biogenesis at the posttranscriptional level in the nucleus evidence for a microRNA hierarchy system Rui Tang 1 2 3 Limin Li 1 Dihan Zhu 1 Dongxia Hou 1 Ting Cao 1 Hongwei Gu 1 Jing Zhang 1 Junyuan Chen 2 Chen Yu Zhang 1 and Ke Zen 1 Cell Research 2012 22 504 515 doi 10 1038 cr 2011 137 published online 23 August 2011 Full Text PDF MicroRNAs miRNAs are endogenous noncoding RNAs 22 nt that regulate target gene expression at the post transcriptional level in the cytoplasm Recent discoveries of the presence of miRNAs and miRNA function required argonaute family proteins in the cell nucleus have prompted us to hypothesize that miRNAs may also have regulatory functions in the cell nucleus In this study we demonstrate that mouse miR 709 is predominantly located in the nucleus of various cell types and that its nuclear localization pattern rapidly changes upon apoptotic stimuli In the cell nucleus miR 709 directly binds to a 19 nt miR 709 recognition element on pri miR 15a 16 1 and prevents its processing into pre miR 15a 16 1 leading to a suppression of miR 15a 16 1 maturation Furthermore nuclear miR 709 participates in the regulation of cell apoptosis through the miR 15a 16 1 pathway In summary the present study provides the first evidence that one miRNA can control the biogenesis of other miRNAs by directly targeting their primary transcripts in the nucleus Cardiomyocyte overexpression of miR 27b induces cardiac hypertrophy and dysfunction in mice Jian Wang 1 Yao Song 2 Yan Zhang 1 Han Xiao 2 Qiang Sun 1 Ning Hou 1 Shuilong Guo 1 Youliang Wang 1 Kaiji Fan 1 Dawei Zhan 3 Lagabaiyila Zha Cell Research 2012 22 516 527 doi 10 1038 cr 2011 132 published online 16 August 2011 Full Text PDF Recent studies have begun to reveal critical roles of microRNAs miRNAs in the pathogenesis of cardiac hypertrophy and dysfunction In this study we tested whether a transforming growth factor β TGF β regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure HF We observed that miR 27b was upregulated in hearts of cardiomyocyte specific Smad4 knockout mice which developed cardiac hypertrophy In vitro experiments showed that the miR 27b expression could be inhibited by TGF β1 and that its overexpression promoted hypertrophic cell growth while the miR 27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine PE treatment Furthermore the analysis of transgenic mice with cardiomyocyte specific overexpression of miR 27b revealed that miR 27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction We validated the peroxisome proliferator activated receptor γ PPAR γ as a direct target of miR 27b in cardiomyocyte Consistently the miR 27b transgenic mice displayed significantly lower levels of PPAR γ than the control mice Furthermore in vivo silencing of miR 27b using a specific antagomir in a pressure overload induced mouse model of HF increased cardiac PPAR γ expression attenuated cardiac hypertrophy and dysfunction The results of our study demonstrate that TGF β1 regulated miR 27b is involved in the regulation of cardiac hypertrophy and validate miR 27b as an efficient therapeutic target for cardiac diseases IL 17 response mediates acute lung injury induced by the 2009 Pandemic Influenza A H1N1 Virus Chenggang Li 1 Penghui Yang 2 Yang Sun 1 Taisheng Li 3 Chen Wang 4 Zhong Wang 5 Zhen Zou 1 Yiwu Yan 1 Wei Wang 1 Chen Wang 1 Zho Cell Research 2012 22 528 538 doi 10 1038 cr 2011 165 published online 25 October 2011 Full Text PDF The 2009 flu pandemic involved the emergence of a new strain of a swine origin H1N1 influenza virus S OIV H1N1 that infected almost every country in the world Most infections resulted in respiratory illness and some severe cases resulted in acute lung injury In this report we are the first to describe a mouse model of S OIV virus infection with acute lung injury and immune responses that reflect human clinical disease The clinical efficacy of the antiviral oseltamivir Tamiflu administered in the early stages of S OIV H1N1 infection was confirmed in the mouse model Moreover elevated levels of IL 17 Th 17 mediators and IL 17 responsive cytokines were found in serum samples of S OIV infected patients in Beijing IL 17 deficiency or treatment with monoclonal antibodies against IL 17 ameliorated acute lung injury induced by the S OIV H1N1 virus in mice These results suggest that IL 17 plays an important role in S OIV induced acute lung injury and that monoclonal antibodies against IL 17 could be useful as a potential therapeutic remedy for future S OIV H1N1 pandemics p38α controls erythroblast enucleation and Rb signaling in stress erythropoiesis Simon M Schultze 2 Andreas Mairhofer 1 Dan Li 2 Jin Cen 2 Hartmut Beug 1 4 Erwin F Wagner 2 and Lijian Hui 2 Cell Research 2012 22 539 550 doi 10 1038 cr 2011 159 published online 27 September 2011 Full Text PDF Enucleation of erythroblasts during terminal differentiation is unique to mammals Although erythroid enucleation has been extensively studied only a few genes including retinoblastoma protein Rb have been identified to regulate nuclear extrusion It remains largely undefined by which signaling molecules the

    Original URL path: http://www.cell-research.com/artsmore.asp?id=16 (2016-02-14)
    Open archived version from archive

  • Cell Research
    that we named osa smR5864w A substitution of C to G in p tms12 1 the only polymorphism relative to P TMS12 1 is present in the mutant small RNA namely osa smR5864m Furthermore overexpression of a 375 bp sequence of P TMS12 1 in transgenic NK58S and PA64S plants also produced osa smR5864w and restored pollen fertility The small RNA was expressed preferentially in young panicles but its expression was not markedly affected by different day lengths or temperatures Our results reveal that the point mutation in p tms12 1 which probably leads to a loss of function for osa smR5864m constitutes a common cause for PGMS and TGMS in the japonica and indica lines respectively Our findings thus suggest that this noncoding small RNA gene is an important regulator of male development controlled by cross talk between the genetic networks and environmental conditions PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus Ting Jin 1 Qiurong Ding 1 Heng Huang 1 Daqian Xu 1 Yuhui Jiang 1 Ben Zhou 1 Zhenghu Li 1 Xiaomeng Jiang 1 Jing He 1 Weizhong Liu 1 Yixua Cell Research 2012 22 661 676 doi 10 1038 cr 2011 161 published online 4 October 2011 Full Text PDF Ras plays a pivotal role in many cellular activities and its subcellular compartmentalization provides spatial and temporal selectivity Here we report a mode of spatial regulation of Ras signaling in the Golgi apparatus by two highly homologous proteins PAQR10 and PAQR11 of the progestin and AdipoQ receptors family PAQR10 and PAQR11 are exclusively localized in the Golgi apparatus Overexpression of PAQR10 PAQR11 stimulates basal and EGF induced ERK phosphorylation and increases the expression of ERK target genes in a dose dependent manner Overexpression of PAQR10 PAQR11 markedly elevates Golgi localization of HRas NRas and KRas4A but not KRas4B PAQR10 and PAQR11 can also interact with HRas NRas and KRas4A but not KRas4B The increased Ras protein at the Golgi apparatus by overexpression of PAQR10 PAQR11 is in an active state Consistently knockdown of PAQR10 and PAQR11 reduces EGF stimulated ERK phosphorylation and Ras activation at the Golgi apparatus Intriguingly PAQR10 and PAQR11 are able to interact with RasGRP1 a guanine nucleotide exchange protein of Ras and increase Golgi localization of RasGRP1 The C1 domain of RasGRP1 is both necessary and sufficient for the interaction of RasGRP1 with PAQR10 PAQR11 The simulation of ERK phosphorylation by overexpressed PAQR10 PAQR11 is abrogated by downregulation of RasGRP1 Furthermore differentiation of PC12 cells is significantly enhanced by overexpression of PAQR10 PAQR11 Collectively this study uncovers a new paradigm of spatial regulation of Ras signaling in the Golgi apparatus by PAQR10 and PAQR11 Endosome mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons Xu Qiao Chen 1 Bin Wang 1 Chengbiao Wu 2 Jin Pan 1 Bo Yuan 3 Yuan Yuan Su 1 Xing Yu Jiang 3 Xu Zhang 4 and Lan Bao 1 Cell Research 2012 22 677 696 doi 10 1038 cr 2011 197 published online 13 December 2011 Full Text PDF Neurotrophins and their receptors adopt signaling endosomes to transmit retrograde signals However the mechanisms of retrograde signaling for other ligand receptor systems are poorly understood Here we report that the signals of the purinergic P 2X 3 receptor an ATP gated ion channel are retrogradely transported in dorsal root ganglion DRG neuron axons We found that Rab5 a small GTPase controls the early sorting of P2X 3 receptors into endosomes while Rab7 mediates the fast retrograde transport of P2X 3 receptors Intraplantar injection and axonal application into the microfluidic chamber of α β methylene ATP α β MeATP a P2X selective agonist enhanced the endocytosis and retrograde transport of P2X 3 receptors The α β MeATP induced Ca 2 influx activated a pathway comprised of protein kinase C rat sarcoma viral oncogene and extracellular signal regulated protein kinase ERK which associated with endocytic P2X 3 receptors to form signaling endosomes Disruption of the lipid rafts abolished the α β MeATP induced ERK phosphorylation endocytosis and retrograde transport of P2X 3 receptors Furthermore treatment of peripheral axons with α β MeATP increased the activation level of ERK and cAMP response element binding protein in the cell bodies of DRG neurons and enhanced neuronal excitability Impairment of either microtubule based axonal transport in vivo or dynein function in vitro blocked α β MeATP induced retrograde signals These results indicate that P2X 3 receptor activated signals are transmitted via retrogradely transported endosomes in primary sensory neurons and provide a novel signaling mechanism for ligand gated channels Shh signaling guides spatial pathfinding of raphespinal tract axons by multidirectional repulsion Lijuan Song 1 2 Yuehui Liu 1 Yang Yu 1 Xin Duan 1 Shening Qi 2 and Yaobo Liu 1 Cell Research 2012 22 697 716 doi 10 1038 cr 2011 172 published online 8 November 2011 Full Text PDF Relatively little is known about the molecular mechanisms underlying spatial pathfinding in the descending serotonergic raphespinal tract RST in the developing spinal cord one of the most important nerve pathways for pain sensory and motor functions We provide evidence that ventral floor plate secreted Sonic hedgehog Shh is responsible for the establishment of decreasing gradients in both the anterior to posterior A P and the medial to lateral M L directions in the ventral spinal cord during serotonergic RST axon projection Downstream components of the Shh pathway Patched 1 Ptch1 and Smoothened Smo were expressed in the serotonergic caudal raphe nuclei and enriched in the descending serotonergic RST axons Diffusible Shh repulsion of serotonergic RST axons was shown to be mediated by Shh Ptch1 interactions and derepression of Smo Using a co culture assay we showed that A P graded repulsion mediated by Shh signaling pushed the serotonergic axons caudally through the ventral spinal cord and M L graded repulsion mediated by Shh signaling simultaneously restricted the serotonergic axons to the ventral and ventral lateral funiculus Prominent pathfinding errors of serotonergic RST axons were observed in various

    Original URL path: http://www.cell-research.com/artsmore.asp?id=15 (2016-02-14)
    Open archived version from archive

  • Cell Research
    IL 6 and IFN β in the sera when they were challenged with LPS or infected with VSV Taken together these results provide in vivo evidence that NLRC5 plays critical roles in MHC class I expression innate immune signaling and antiviral innate immune responses thus serving as an important target for modulating innate immune signaling and regulation NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens Yikun Yao 1 Yalong Wang 1 Fuxiang Chen 2 Yin Huang 1 Shu Zhu 1 Qibin Leng 3 Hongyan Wang 4 Yufang Shi 1 and Youcun Qian 1 Cell Research 2012 22 836 847 doi 10 1038 cr 2012 56 published online 10 April 2012 Full Text PDF NOD like receptors NLRs are a family of intracellular proteins that play critical roles in innate immunity against microbial infection NLRC5 the largest member of the NLR family has recently attracted much attention However in vitro studies have reported inconsistent results about the roles of NLRC5 in host defense and in regulating immune signaling pathways The in vivo function of NLRC5 remains unknown Here we report that NLRC5 is a critical regulator of host defense against intracellular pathogens in vivo NLRC5 was specifically required for the expression of genes involved in MHC class I antigen presentation NLRC5 deficient mice showed a profound defect in the expression of MHC class I genes and a concomitant failure to activate L monocytogenes specific CD8 T cell responses including activation proliferation and cytotoxicity and the mutant mice were more susceptible to the pathogen infection NLRP3 mediated inflammasome activation was also partially impaired in NLRC5 deficient mice However NLRC5 was dispensable for pathogen induced expression of NF κB dependent pro inflammatory genes as well as type I interferon genes Thus NLRC5 critically regulates MHC class I antigen presentation to control intracellular pathogen infection Evidence for a critical role of gene occlusion in cell fate restriction Jedidiah Gaetz 1 Kayla L Clift 1 Croydon J Fernandes 1 Frank Fuxiang Mao 1 2 Jae Hyun Lee 1 Li Zhang 1 Samuel W Baker 1 Timothy J Looney 1 Kara M Foshay 1 Cell Research 2012 22 848 858 doi 10 1038 cr 2011 190 published online 29 November 2011 Full Text PDF The progressive restriction of cell fate during lineage differentiation is a poorly understood phenomenon despite its ubiquity in multicellular organisms We recently used a cell fusion assay to define a mode of epigenetic silencing that we termed occlusion wherein affected genes are silenced by cis acting chromatin mechanisms irrespective of whether trans acting transcriptional activators are present We hypothesized that occlusion of lineage inappropriate genes could contribute to cell fate restriction Here we test this hypothesis by introducing bacterial artificial chromosomes BACs which are devoid of chromatin modifications necessary for occlusion into mouse fibroblasts We found that BAC transgenes corresponding to occluded endogenous genes are expressed in most cases whereas BAC transgenes corresponding to silent but non occluded endogenous genes are not expressed This indicates that the cellular milieu in trans supports the expression of most occluded genes in fibroblasts and that the silent state of these genes is solely the consequence of occlusion in cis For the BAC corresponding to the occluded myogenic master regulator Myf5 expression of the Myf5 transgene on the BAC triggered fibroblasts to acquire a muscle like phenotype These results provide compelling evidence for a critical role of gene occlusion in cell fate restriction A distinct response to endogenous DNA damage in the development of Nbs1 deficient cortical neurons Rui Li 1 Yun Gui Yang 2 Yunzhou Gao 1 Zhao Qi Wang 3 4 and Wei Min Tong 1 Cell Research 2012 22 859 872 doi 10 1038 cr 2012 3 published online 3 January 2012 Full Text PDF Microcephaly is a clinical characteristic for human nijmegen breakage syndrome NBS mutated in NBS1 gene a chromosomal instability syndrome However the underlying molecular pathogenesis remains elusive In the present study we demonstrate that neuronal disruption of NBS Nbn in mice causes microcephaly characterized by the reduction of cerebral cortex and corpus callosum recapitulating neuronal anomalies in human NBS Nbs1 deficient neocortex shows accumulative endogenous DNA damage and defective activation of Ataxia telangiectasia and Rad3 related ATR Chk1 pathway upon DNA damage Notably in contrast to massive apoptotic cell death in Nbs1 deficient cerebella activation of p53 leads to a defective neuroprogenitor proliferation in neocortex likely via specific persistent induction of hematopoietic zinc finger Hzf that preferentially promotes p53 mediated cell cycle arrest whilst inhibiting apoptosis Moreover Trp53 mutations substantially rescue the microcephaly in Nbs1 deficient mice Thus the present results reveal the first clue that developing neurons at different regions of brain selectively respond to endogenous DNA damage and underscore an important role for Nbs1 in neurogenesis Akt is negatively regulated by the MULAN E3 ligase Seunghee Bae 1 Sun Yong Kim 1 Jin Hyuk Jung 1 Yeongmin Yoon 1 2 Hwa Jun Cha 1 Hyunjin Lee 1 2 Karam Kim 1 Jongran Kim 1 In Sook An 1 Jongdoo Kim Cell Research 2012 22 873 885 doi 10 1038 cr 2012 38 published online 13 March 2012 Full Text PDF The serine threonine kinase Akt functions in multiple cellular processes including cell survival and tumor development Studies of the mechanisms that negatively regulate Akt have focused on dephosphorylation mediated inactivation In this study we identified a negative regulator of Akt MULAN which possesses both a RING finger domain and E3 ubiquitin ligase activity Akt was found to directly interact with MULAN and to be ubiquitinated by MULAN in vitro and in vivo Other molecular assays demonstrated that phosphorylated Akt is a substantive target for both interaction with MULAN and ubiquitination by MULAN The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability These data provide insight into the Akt ubiquitination signaling network MRG 1 is required for genomic integrity in Caenorhabditis elegans germ cells Jing Xu 1 3 Xiaojuan Sun 1 3 Yudong

    Original URL path: http://www.cell-research.com/artsmore.asp?id=14 (2016-02-14)
    Open archived version from archive

  • Cell Research
    to transform hESC derived hematopoietic cells This work illustrates how hESCs may provide unique insights into human development and further our understanding of how leukemic fusion genes known to arise prenatally regulate human embryonic hematopoietic specification Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor Mei Yi Wu 1 Junjiang Fu 2 Jianming Xu 3 Bert W O Malley 3 and Ray Chang Wu 1 3 10 1038 cr 2012 44 published online 20 March 2012 SRC 3 AIB1 steroid receptor coactivator 3 amplified in breast cancer 1 is an authentic oncogene that contributes to the development of drug resistance and poor disease free survival in cancer patients Autophagy is also an important cell death mechanism that has tumor suppressor function In this study we identified macrophage migration inhibitory factor MIF as a novel target gene of SRC 3 and demonstrated its importance in cell survival Specifically we showed that MIF is a strong suppressor of autophagic cell death We further showed that suppression of MIF in turn induced autophagic cell death enhanced chemosensitivity and inhibited tumorigenesis in a xenograft mouse tumorigenesis model Our study demonstrated that regulation of MIF expression and suppression of autophagic cell death is a potent mechanism by which SRC 3 contributes to increased chemoresistance and tumorigenicity Microglial migration mediated by ATP induced ATP release from lysosomes Ying Dou 1 Hang jun Wu 2 3 Hui quan Li 2 Song Qin 1 Yin er Wang 2 Jing Li 2 Hui fang Lou 2 Zhong Chen 2 Xiao ming Li 2 Qing ming Luo 3 an Cell Research 2012 22 1022 1033 doi 10 1038 cr 2012 10 published online 10 January 2012 Full Text PDF Microglia are highly motile cells that act as the main form of active immune defense in the central nervous system Attracted by factors released from damaged cells microglia are recruited towards the damaged or infected site where they are involved in degenerative and regenerative responses and phagocytotic clearance of cell debris ATP release from damaged neural tissues has been suggested to mediate the rapid extension of microglial process towards the site of injury However the mechanisms of the long range migration of microglia remain to be clarified Here we found that lysosomes in microglia contain abundant ATP and exhibit Ca 2 dependent exocytosis in response to various stimuli By establishing an efficient in vitro chemotaxis assay we demonstrated that endogenously released ATP from microglia triggered by local microinjection of ATPγS is critical for the long range chemotaxis of microglia a response that was significantly inhibited in microglia treated with an agent inducing lysosome osmodialysis or in cells derived from mice deficient in Rab 27a ashen mice a small GTPase required for the trafficking and exocytosis of secretory lysosomes These results suggest that microglia respond to extracellular ATP by releasing ATP themselves through lysosomal exocytosis thereby providing a positive feedback mechanism to generate a long range extracellular signal for attracting distant microglia to migrate towards and

    Original URL path: http://www.cell-research.com/artsmore.asp?id=13 (2016-02-14)
    Open archived version from archive

  • Cell Research
    on disease severity upon genetic or pharmacological manipulations Hopefully some of these findings will lead to the development of novel therapies for MS in the near future ORIGINAL ARTICLES Phospholipid Scramblase 1 regulates Toll like receptor 9 mediated type I interferon production in plasmacytoid dendritic cells Amjad H Talukder Musheng Bao Tae Whan Kim Valeria Facchinetti Shino Hanabuchi Laura Bover Tomasz Zal and Yong Jun Liu Cell Research 2012 22 1129 1139 doi 10 1038 cr 2012 45 published online 27 March 2012 Full Text PDF Toll like receptor 9 TLR9 senses microbial DNA in the endosomes of plasmacytoid dendritic cells pDCs and triggers MyD88 dependent type I interferon IFN responses To better understand TLR9 biology in pDCs we established a yeast two hybrid library for the identification of TLR9 interacting proteins Here we report that an IFN inducible protein phospholipid scramblase 1 PLSCR1 interacts with TLR9 in pDCs Knockdown of PLSCR1 expression by siRNA in human pDC cell line led to a 60 70 reduction of IFN α responses following CpG ODN oligodeoxynucleotide stimulation Primary pDCs from PLSCR1 deficient mice produced lower amount of type 1 IFN than pDCs from the wild type mice in response to CpG ODN herpes simplex virus and influenza A virus Following CpG A stimulation there were much lower amounts of TLR9 in the early endosomes together with CpG A in pDCs from PLSCR1 deficient mice Our study demonstrates that PLSCR1 is a TLR9 interacting protein that plays an important role in pDC s type 1 IFN responses by regulating TLR9 trafficking to the endosomal compartment Misfolded Gβ is recruited to cytoplasmic dynein by Nudel for efficient clearance Yihan Wan Zhenye Yang Jing Guo Qiangge Zhang Liyong Zeng Wei Song Yue Xiao and Xueliang Zhu Cell Research 2012 22 1140 1154 doi 10 1038 cr 2012 41 published online 20 March 2012 Full Text PDF The Gβγ heterodimer is an important signal transducer Gβ however is prone to misfolding due to its requirement for Gγ and chaperones for proper folding How cells dispose of misfolded Gβ mfGβ is not clear Here we showed that mfGβ was able to be polyubiquitinated and subsequently degraded by the proteasome It was sequestered in aggresomes after the inhibition of the proteasome activity with MG132 Sustained activation of Gβγ signaling further elevated cellular levels of the ubiquitinated Gβ Moreover Nudel a regulator of cytoplasmic dynein the microtubule minus end directed motor directly interacted with both the unubiquitinated and ubiquitinated mfGβ Increasing the levels of both mfGβ and Nudel promoted the association of Gβ with both Nudel and dynein resulting in robust aggresome formation in a dynein dependent manner Depletion of Nudel by RNAi reduced the dynein associated mfGβ impaired the MG132 induced aggresome formation and markedly prolonged the half life of nascent Gβ Therefore cytosolic mfGβ is recruited to dynein by Nudel and transported to the centrosome for rapid sequestration and degradation Such a process not only eliminates mfGβ efficiently for the control of protein quality but may also

    Original URL path: http://www.cell-research.com/artsmore.asp?id=12 (2016-02-14)
    Open archived version from archive



  •