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PubMed Central (PMC3 - NLM DTD) (2.616.353 recursos)
Archive of life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH's National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM).

Mostrando recursos 1 - 20 de 876

1. Gain of function in the immune system caused by a ryanodine receptor 1 mutation - Vukcevic, Mirko; Zorzato, Francesco; Keck, Simone; Tsakiris, Dimitrios A.; Keiser, Jennifer; Maizels, Rick M.; Treves, Susan
Mutations in RYR1, the gene encoding ryanodine receptor 1, are linked to a variety of neuromuscular disorders including malignant hyperthermia (MH), a pharmacogenetic hypermetabolic disease caused by dysregulation of Ca2+ in skeletal muscle. RYR1 encodes a Ca2+ channel that is predominantly expressed in skeletal muscle sarcoplasmic reticulum, where it is involved in releasing the Ca2+ necessary for muscle contraction. Other tissues, however, including cells of the immune system, have been shown to express ryanodine receptor 1; in dendritic cells its activation leads to increased surface expression of major histocompatibility complex II molecules and provides synergistic signals leading to cell maturation....

2. Par6γ is at the mother centriole and controls centrosomal protein composition through a Par6α-dependent pathway - Dormoy, Valérian; Tormanen, Kati; Sütterlin, Christine
The centrosome contains two centrioles that differ in age, protein composition and function. This non-membrane bound organelle is known to regulate microtubule organization in dividing cells and ciliogenesis in quiescent cells. These specific roles depend on protein appendages at the older, or mother, centriole. In this study, we identified the polarity protein partitioning defective 6 homolog gamma (Par6γ) as a novel component of the mother centriole. This specific localization required the Par6γ C-terminus, but was independent of intact microtubules, the dynein/dynactin complex and the components of the PAR polarity complex. Par6γ depletion resulted in altered centrosomal protein composition, with the...

3. ifet-1 is a broad-scale translational repressor required for normal P granule formation in C. elegans - Sengupta, Madhu S.; Low, Wai Yee; Patterson, Joseph R.; Kim, Hyun-Min; Traven, Ana; Beilharz, Traude H.; Colaiácovo, Monica P.; Schisa, Jennifer A.; Boag, Peter R.
Large cytoplasmic ribonucleoprotein germ granule complexes are a common feature in germ cells. In C. elegans these are called P granules and for much of the life-cycle they associate with nuclear pore complexes in germ cells. P granules are rich in proteins that function in diverse RNA pathways. Here we report that the C. elegans homolog of the eIF4E-transporter IFET-1 is required for oogenesis but not spermatogenesis. We show that IFET-1 is required for translational repression of several maternal mRNAs in the distal gonad and functions in conjunction with the broad-scale translational regulators CGH-1, CAR-1 and PATR-1 to regulate germ...

4. MTR120/KIAA1383, a novel microtubule-associated protein, promotes microtubule stability and ensures cytokinesis - Fong, Ka-wing; Leung, Justin Wai-chung; Li, Yujing; Wang, Wenqi; Feng, Lin; Ma, Wenbin; Liu, Dan; Songyang, Zhou; Chen, Junjie
Microtubules (MTs) are the major constituent of the mitotic apparatus. Deregulation of MT dynamics leads to chromosome missegregation, cytokinesis failure and improper inheritance of genetic materials. Here, we describe the identification and characterization of KIAA1383/MTR120 (microtubule regulator 120 kDa) as a novel MT-associated protein. We found that MTR120 localizes to stabilized MTs during interphase and to the mitotic apparatus during mitosis. MTR120 overexpression results in MT bundling and acetylation. In vitro, purified MTR120 protein binds to and bundles preassembled MTs. Moreover, depletion of MTR120 by RNA interference leads to cytokinesis failure and polyploidy. These phenotypes can be rescued by wild-type MTR120...

5. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity - Qi, Xin; Qvit, Nir; Su, Yu-Chin; Mochly-Rosen, Daria
Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Using a rational approach, we designed a novel and selective peptide inhibitor, P110, of excessive mitochondrial fission. P110 inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons, whereas it has no effect on the interaction between Drp1 and other mitochondrial adaptors, as demonstrated by co-immunoprecipitation. Furthermore, using a model of Parkinson's disease (PD) in culture, we demonstrated that P110 is neuroprotective by...

6. Separate roles of PKA and EPAC in renal function unraveled by the optogenetic control of cAMP levels in vivo - Efetova, Marina; Petereit, Linda; Rosiewicz, Kamil; Overend, Gayle; Haußig, Florian; Hovemann, Bernhard T.; Cabrero, Pablo; Dow, Julian A. T.; Schwärzel, Martin
Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates a variety of essential processes in diverse cell types, functioning via cAMP-dependent effectors such as protein kinase A (PKA) and/or exchange proteins directly activated by cAMP (EPAC). In an intact tissue it is difficult to separate the contribution of each cAMP effector in a particular cell type using genetic or pharmacological approaches alone. We, therefore, utilized optogenetics to overcome the difficulties associated with examining a multicellular tissue. The transgenic photoactive adenylyl cyclase bPAC can be activated to rapidly and reversibly generate cAMP pulses in a cell-type-specific manner. This optogenetic approach...

7. PtdIns(3,4,5)P3 is constitutively synthesized and required for spindle translocation during meiosis in mouse oocytes - Zheng, Ping; Baibakov, Boris; Wang, Xi-hong; Dean, Jurrien
Prior to ovulation, mammalian oocytes complete their first meiotic division and arrest at metaphase II. During this marked asymmetric cell division, the meiotic spindle moves dramatically from the center of the oocyte to the cortex to facilitate segregation of half of its chromosomal content into the diminutive first polar body. Recent investigations have documented crucial roles for filamentous actin (F-actin) in meiotic spindle translocation. However, the identity of the upstream regulators responsible for these carefully orchestrated movements has remained elusive. Utilizing fluorescently tagged probes and time-lapse confocal microscopy, we document that phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] is constitutively synthesized with spatial and...

8. PML isoforms in response to arsenic: high-resolution analysis of PML body structure and degradation - Hands, Katherine J.; Cuchet-Lourenco, Delphine; Everett, Roger D.; Hay, Ronald T.
Arsenic is a clinically effective treatment for acute promyelocytic leukaemia (APL) in which the promyelocytic leukaemia (PML) protein is fused to retinoic receptor alpha (RARα). PML-RARα is degraded by the proteasome by a SUMO-dependent, ubiquitin-mediated pathway in response to arsenic treatment, curing the disease. Six major PML isoforms are expressed as a result of alternative splicing, each of which encodes a unique C-terminal region. Using a system in which only a single EYFP-linked PML isoform is expressed, we demonstrate that PMLI, PMLII and PMLVI accumulate in the cytoplasm following arsenic treatment, whereas PMLIII, PMLIV and PMLV do not. 3D structured...

9. A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function - Trebble, Peter J.; Woolven, James M.; Saunders, Ken A.; Simpson, Karen D.; Farrow, Stuart N.; Matthews, Laura C.; Ray, David W.
The ubiquitously expressed glucocorticoid receptor (GR) is a major drug target for inflammatory disease, but issues of specificity and target tissue sensitivity remain. We now identify high potency, non-steroidal GR ligands, GSK47867A and GSK47869A, which induce a novel conformation of the GR ligand-binding domain (LBD) and augment the efficacy of cellular action. Despite their high potency, GSK47867A and GSK47869A both induce surprisingly slow GR nuclear translocation, followed by prolonged nuclear GR retention, and transcriptional activity following washout. We reveal that GSK47867A and GSK47869A specifically alter the GR LBD structure at the HSP90-binding site. The alteration in the HSP90-binding site was...

10. Preferential invasion of mitotic cells by Salmonella reveals that cell surface cholesterol is maximal during metaphase - Santos, António J. M.; Meinecke, Michael; Fessler, Michael B.; Holden, David W.; Boucrot, Emmanuel
Cell surface-exposed cholesterol is crucial for cell attachment and invasion of many viruses and bacteria, including the bacterium Salmonella, which causes typhoid fever and gastroenteritis. Using flow cytometry and 3D confocal fluorescence microscopy, we found that mitotic cells, although representing only 1–4% of an exponentially growing population, were much more efficiently targeted for invasion by Salmonella. This targeting was not dependent on the spherical shape of mitotic cells, but was instead SipB and cholesterol dependent. Thus, we measured the levels of plasma membrane and cell surface cholesterol throughout the cell cycle using, respectively, brief staining with filipin and a fluorescent...

11. Role of Ser129 phosphorylation of α-synuclein in melanoma cells - Lee, Byung Rho; Matsuo, Yasuhiro; Cashikar, Anil G.; Kamitani, Tetsu
α-Synuclein, a protein central to Parkinson's disease, is frequently expressed in melanoma tissues, but not in non-melanocytic cutaneous carcinoma and normal skin. Thus, α-synuclein is not only related to Parkinson's disease, but also to melanoma. Recently, epidemiologists reported co-occurrence of melanoma and Parkinson's disease in patients, suggesting that these diseases could share common pathogenetic components and that α-synuclein might be one of these. In Parkinson's disease, phosphorylation of α-synuclein at Ser129 plays an important role in the pathobiology. However, its role in melanoma is not known. Here, we show the biological relevance of Ser129 phosphorylation in human melanoma cells. First,...

12. Plexin B1 inhibits MET through direct association and regulates Shp2 expression in melanocytes - Soong, Joanne; Scott, Glynis
Plexin B1, the receptor for Semaphorin 4D (Sema4D), is expressed by melanocytes in the skin. We recently showed that Sema4D suppresses activation of the hepatocyte growth factor receptor, MET, in melanocytes, and that knockdown of Plexin B1 results in activation of MET. MET signaling mediates proliferation, survival and migration in melanocytes, and its activation is associated with transformation of melanocytes to melanoma. In this report we investigated the mechanism by which Plexin B1 inhibits MET activation. Our results show that Plexin B1 and MET exist as an oligomeric receptor-receptor complex in melanocytes, and that receptor association is increased by Sema4D....

13. Impairment of TRPC1–STIM1 channel assembly and AQP5 translocation compromise agonist-stimulated fluid secretion in mice lacking caveolin1 - Pani, Biswaranjan; Liu, Xibao; Bollimuntha, Sunitha; Cheng, Kwong Tai; Niesman, Ingrid R.; Zheng, Changyu; Achen, Virginia R.; Patel, Hemal H.; Ambudkar, Indu S.; Singh, Brij B.
Neurotransmitter regulation of salivary fluid secretion is mediated by activation of Ca2+ influx. The Ca2+-permeable transient receptor potential canonical 1 (TRPC1) channel is crucial for fluid secretion. However, the mechanism(s) involved in channel assembly and regulation are not completely understood. We report that Caveolin1 (Cav1) is essential for the assembly of functional TRPC1 channels in salivary glands (SG) in vivo and thus regulates fluid secretion. In Cav1−/− mouse SG, agonist-stimulated Ca2+ entry and fluid secretion are significantly reduced. Microdomain localization of TRPC1 and interaction with its regulatory protein, STIM1, are disrupted in Cav1−/− SG acinar cells, whereas Orai1–STIM1 interaction is...

14. Role of STIM1- and Orai1-mediated Ca2+ entry in Ca2+-induced epidermal keratinocyte differentiation - Numaga-Tomita, Takuro; Putney, James W.
The uppermost thin layer on the surface of the skin, called the epidermis, is responsible for the barrier function of the skin. The epidermis has a multilayered structure in which each layer consists of keratinocytes (KCs) of different differentiation status. The integrity of KC differentiation is crucial for the function of skin and its loss causes or is accompanied by skin diseases. Intracellular and extracellular Ca2+ is known to play important roles in KC differentiation. However, the molecular mechanisms underlying Ca2+ regulation of KC differentiation are still largely unknown. Store-operated Ca2+ entry (SOCE) is a major Ca2+ influx pathway in...

15. BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells - Hu, Ning; Jiang, Dianming; Huang, Enyi; Liu, Xing; Li, Ruidong; Liang, Xi; Kim, Stephanie H.; Chen, Xiang; Gao, Jian-Li; Zhang, Hongyu; Zhang, Wenwen; Kong, Yu-Han; Zhang, Jiye; Wang, Jinhua; Shui, Wei; Luo, Xiaoji; Liu, Bo; Cui, Jing; Rogers, Mary Rose; Shen, Jikun; Zhao, Chen; Wang, Ning; Wu, Ningning; Luu, Hue H.; Haydon, Rex C.; He, Tong-Chuan; Huang, Wei
Mesenchymal stromal progenitor cells (MSCs) are multipotent progenitors that can be isolated from numerous tissues. MSCs can undergo osteogenic differentiation under proper stimuli. We have recently demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most osteogenic BMPs. As one of the least studied BMPs, BMP9 has been shown to regulate angiogenesis in endothelial cells. However, it is unclear whether BMP9-regulated angiogenic signaling plays any important role in the BMP9-initiated osteogenic pathway in MSCs. Here, we investigate the functional role of hypoxia-inducible factor 1α (HIF1α)-mediated angiogenic signaling in BMP9-regulated osteogenic differentiation of MSCs. We find that BMP9 induces...

16. Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion - Sengupta, Pritam K.; Bouchie, Meghan P.; Nita-Lazar, Mihai; Yang, Hsiao-Ying; Kukuruzinska, Maria A.
The metabolic pathway of protein N-glycosylation influences intercellular adhesion by affecting the composition and cytoskeletal association of E-cadherin protein complexes, or adherens junctions (AJs). In sparse cells, E-cadherin is modified extensively with complex N-glycans and forms nascent AJs, while in dense cultures, hypoglycosylated E-cadherin drives the assembly of mature AJs with increased levels of γ- and α-catenins. N-glycosylation of E-cadherin is controlled by the DPAGT1 gene, a key regulator of the N-glycosylation pathway. DPAGT1 is a target of the canonical Wnt signaling pathway, with both β- and γ-catenins binding to Tcf at its promoter. We now report that DPAGT1 senses...

17. A non-catalytic role for inositol 1,3,4,5,6-pentakisphosphate 2-kinase in the synthesis of ribosomal RNA - Brehm, Maria A.; Wundenberg, Torsten; Williams, Jason; Mayr, Georg W.; Shears, Stephen B.
Fundamental to the life and destiny of every cell is the regulation of protein synthesis through ribosome biogenesis, which begins in the nucleolus with the production of ribosomal RNA (rRNA). Nucleolar organization is a highly dynamic and tightly regulated process; the structural factors that direct nucleolar assembly and disassembly are just as important in controlling rRNA synthesis as are the catalytic activities that synthesize rRNA. Here, we report that a signaling enzyme, inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IP5K) is also a structural component in the nucleolus. We demonstrate that IP5K has functionally significant interactions with three proteins that regulate rRNA synthesis: protein...

18. Epithelial–mesenchymal status influences how cells deposit fibrillin microfibrils - Baldwin, Andrew K.; Cain, Stuart A.; Lennon, Rachel; Godwin, Alan; Merry, Catherine L. R.; Kielty, Cay M.
Here, we show that epithelial–mesenchymal status influences how cells deposit extracellular matrix. Retinal pigmented epithelial (RPE) cells that expressed high levels of E-cadherin and had cell–cell junctions rich in zona occludens (ZO)-1, β-catenin and heparan sulfate, required syndecan-4 but not fibronectin or protein kinase C α (PKCα) to assemble extracellular matrix (fibrillin microfibrils and perlecan). In contrast, RPE cells that strongly expressed mesenchymal smooth muscle α-actin but little ZO-1 or E-cadherin, required fibronectin (like fibroblasts) and PKCα, but not syndecan-4. Integrins α5β1 and/or α8β1 and actomyosin tension were common requirements for microfibril deposition, as was heparan sulfate biosynthesis. TGFβ, which...

19. Biased inheritance of mitochondria during asymmetric cell division in the mouse oocyte - Dalton, Caroline M.; Carroll, John
A fundamental rule of cell division is that daughter cells inherit half the DNA complement and an appropriate proportion of cellular organelles. The highly asymmetric cell divisions of female meiosis present a different challenge because one of the daughters, the polar body, is destined to degenerate, putting at risk essential maternally inherited organelles such as mitochondria. We have therefore investigated mitochondrial inheritance during the meiotic divisions of the mouse oocyte. We find that mitochondria are aggregated around the spindle by a dynein-mediated mechanism during meiosis I, and migrate together with the spindle towards the oocyte cortex. However, at cell division...

20. Spatiotemporal organization of Aurora-B by APC/CCdh1 after mitosis coordinates cell spreading through FHOD1 - Floyd, Suzanne; Whiffin, Nicola; Gavilan, Maria P.; Kutscheidt, Stefan; De Luca, Maria; Marcozzi, Chiara; Min, Mingwei; Watkins, Johnathan; Chung, Kathryn; Fackler, Oliver T.; Lindon, Catherine
Spatiotemporal regulation of mitotic kinase activity underlies the extensive rearrangement of cellular components required for cell division. One highly dynamic mitotic kinase is Aurora-B (AurB), which has multiple roles defined by the changing localisation of the chromosome passenger complex (CPC) as cells progress through mitosis, including regulation of cytokinesis and abscission. Like other mitotic kinases, AurB is a target of the anaphase-promoting complex (APC/C) ubiquitin ligase during mitotic exit, but it is not known if APC/C-mediated destruction plays any specific role in controlling AurB activity. We have examined the contribution of the Cdh1 coactivator-associated APC/CCdh1 to the organization of AurB...

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