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Articles 1 - 17 of 17

Full-Text Articles in Cell Biology

Cellular Differentiation Of Human Monocytes Is Regulated By Time-Dependent Interleukin-4 Signaling And The Transcriptional Regulator Ncor2, Jil Sander, Eicke Latz, Andreas Schlitzer Dec 2017

Cellular Differentiation Of Human Monocytes Is Regulated By Time-Dependent Interleukin-4 Signaling And The Transcriptional Regulator Ncor2, Jil Sander, Eicke Latz, Andreas Schlitzer

Open Access Articles

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic ...


Disc1 Modulates Neuronal Stress Responses By Gate-Keeping Er-Mitochondria Ca(2+) Transfer Through The Mam, Sung Jin Park, Su Been Lee, Yeongjun Suh, Su-Jeong Kim, Namgyu Lee, Ji-Ho Hong, Cana Park, Youngsik Woo, Koko Ishizuka, Joung-Hun Kim, Per-Olof Berggren, Akira Sawa, Sang Ki Park Dec 2017

Disc1 Modulates Neuronal Stress Responses By Gate-Keeping Er-Mitochondria Ca(2+) Transfer Through The Mam, Sung Jin Park, Su Been Lee, Yeongjun Suh, Su-Jeong Kim, Namgyu Lee, Ji-Ho Hong, Cana Park, Youngsik Woo, Koko Ishizuka, Joung-Hun Kim, Per-Olof Berggren, Akira Sawa, Sang Ki Park

Open Access Articles

A wide range of Ca(2+)-mediated functions are enabled by the dynamic properties of Ca(2+), all of which are dependent on the endoplasmic reticulum (ER) and mitochondria. Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that is involved in the function of intracellular organelles and is linked to cognitive and emotional deficits. Here, we demonstrate that DISC1 localizes to the mitochondria-associated ER membrane (MAM). At the MAM, DISC1 interacts with IP3R1 and downregulates its ligand binding, modulating ER-mitochondria Ca(2+) transfer through the MAM. The disrupted regulation of Ca(2+) transfer caused by DISC1 dysfunction leads to abnormal Ca ...


Sodium Channel Nav1.3 Is Important For Enterochromaffin Cell Excitability And Serotonin Release, Peter R. Strege, Kaitlyn Knutson, Samuel J. Eggers, Joyce H. Li, Fan Wang, David Linden, Joseph H. Szurszewski, Lorin Milescu, Andrew B. Leiter, Gianrico Farrugia, Arthur Beyder Nov 2017

Sodium Channel Nav1.3 Is Important For Enterochromaffin Cell Excitability And Serotonin Release, Peter R. Strege, Kaitlyn Knutson, Samuel J. Eggers, Joyce H. Li, Fan Wang, David Linden, Joseph H. Szurszewski, Lorin Milescu, Andrew B. Leiter, Gianrico Farrugia, Arthur Beyder

Open Access Articles

In the gastrointestinal (GI) epithelium, enterochromaffin (EC) cells are enteroendocrine cells responsible for producing > 90% of the body's serotonin (5-hydroxytryptamine, 5-HT). However, the molecular mechanisms of EC cell function are poorly understood. Here, we found that EC cells in mouse primary cultures fired spontaneous bursts of action potentials. We examined the repertoire of voltage-gated sodium channels (NaV) in fluorescence-sorted mouse EC cells and found that Scn3a was highly expressed. Scn3a-encoded NaV1.3 was specifically and densely expressed at the basal side of both human and mouse EC cells. Using electrophysiology, we found that EC cells expressed robust NaV1.3 ...


Age-Dependent Human Beta Cell Proliferation Induced By Glucagon-Like Peptide 1 And Calcineurin Signaling, Chunhua Dai, Yan Hang, Alena Shostak, Greg Poffenberger, Nathaniel Hart, Nripesh Prasad, Neil Phillips, Shawn E. Levy, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Seung K. Kim, Alvin C. Powers Oct 2017

Age-Dependent Human Beta Cell Proliferation Induced By Glucagon-Like Peptide 1 And Calcineurin Signaling, Chunhua Dai, Yan Hang, Alena Shostak, Greg Poffenberger, Nathaniel Hart, Nripesh Prasad, Neil Phillips, Shawn E. Levy, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Seung K. Kim, Alvin C. Powers

Open Access Articles

Inadequate pancreatic beta cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human beta cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of beta cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human beta cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 ...


Regulation Of Ripk1 Activation By Tak1-Mediated Phosphorylation Dictates Apoptosis And Necroptosis, Jiefei Geng, Yasushi Ito, Linyu Shi, Palak Amin, Jiachen Chu, Amanda Tomie Ouchida, Adnan Kasim Mookhtiar, Heng Zhao, Daichao Xu, Bing Shan, Ayaz Najafov, Guangping Gao, Shizuo Akira, Junying Yuan Aug 2017

Regulation Of Ripk1 Activation By Tak1-Mediated Phosphorylation Dictates Apoptosis And Necroptosis, Jiefei Geng, Yasushi Ito, Linyu Shi, Palak Amin, Jiachen Chu, Amanda Tomie Ouchida, Adnan Kasim Mookhtiar, Heng Zhao, Daichao Xu, Bing Shan, Ayaz Najafov, Guangping Gao, Shizuo Akira, Junying Yuan

Open Access Articles

Stimulation of TNFR1 by TNFalpha can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFalpha-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFalpha leads to RIPK1-independent apoptosis when NF-kappaB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA ...


Replication Fork Slowing And Stalling Are Distinct, Checkpoint-Independent Consequences Of Replicating Damaged Dna, Divya Ramalingam Iyer, Nicholas R. Rhind Aug 2017

Replication Fork Slowing And Stalling Are Distinct, Checkpoint-Independent Consequences Of Replicating Damaged Dna, Divya Ramalingam Iyer, Nicholas R. Rhind

Open Access Articles

In response to DNA damage during S phase, cells slow DNA replication. This slowing is orchestrated by the intra-S checkpoint and involves inhibition of origin firing and reduction of replication fork speed. Slowing of replication allows for tolerance of DNA damage and suppresses genomic instability. Although the mechanisms of origin inhibition by the intra-S checkpoint are understood, major questions remain about how the checkpoint regulates replication forks: Does the checkpoint regulate the rate of fork progression? Does the checkpoint affect all forks, or only those encountering damage? Does the checkpoint facilitate the replication of polymerase-blocking lesions? To address these questions ...


Alcohol And Cancer: Mechanisms And Therapies, Anuradha Ratna, Pranoti Mandrekar Aug 2017

Alcohol And Cancer: Mechanisms And Therapies, Anuradha Ratna, Pranoti Mandrekar

Open Access Articles

Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1)-mediated generation of reactive oxygen species, aberrant metabolism of folate and retinoids, increased estrogen, and genetic polymorphisms. Here, we summarize the impact of alcohol drinking on the risk of cancer development and potential underlying molecular mechanisms. The interactions between alcohol abuse, anti-tumor immune response, tumor growth, and metastasis are complex. However, multiple studies have linked the immunosuppressive effects ...


Killers Creating New Life: Caspases Drive Apoptosis-Induced Proliferation In Tissue Repair And Disease, Caitlin E. Fogarty, Andreas Bergmann Aug 2017

Killers Creating New Life: Caspases Drive Apoptosis-Induced Proliferation In Tissue Repair And Disease, Caitlin E. Fogarty, Andreas Bergmann

Open Access Articles

Apoptosis is a carefully orchestrated and tightly controlled form of cell death, conserved across metazoans. As the executioners of apoptotic cell death, cysteine-dependent aspartate-directed proteases (caspases) are critical drivers of this cellular disassembly. Early studies of genetically programmed cell death demonstrated that the selective activation of caspases induces apoptosis and the precise elimination of excess cells, thereby sculpting structures and refining tissues. However, over the past decade there has been a fundamental shift in our understanding of the roles of caspases during cell death-a shift precipitated by the revelation that apoptotic cells actively engage with their surrounding environment throughout the ...


Global Increase In Replication Fork Speed During A P57kip2-Regulated Erythroid Cell Fate Switch, Yung Hwang, Melinda Futran, Daniel Hidalgo, Ramona Pop, Divya Ramalingam Iyer, Ralph Scully, Nicholas R. Rhind, Merav Socolovsky May 2017

Global Increase In Replication Fork Speed During A P57kip2-Regulated Erythroid Cell Fate Switch, Yung Hwang, Melinda Futran, Daniel Hidalgo, Ramona Pop, Divya Ramalingam Iyer, Ralph Scully, Nicholas R. Rhind, Merav Socolovsky

Open Access Articles

Cell cycle regulators are increasingly implicated in cell fate decisions, such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. We studied an S phase-dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. We found that progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase inhibitors. The switch to differentiation entails rapid down-regulation of p57KIP2 with a ...


Atorvastatin Promotes Phagocytosis And Attenuates Pro-Inflammatory Response In Human Retinal Pigment Epithelial Cells, Bo Tian, Ahmad Al-Moujahed, Peggy Bouzika, Yijun Hu, Shoji Notomi, Pavlina Tsoka, Joan W. Miller, Haijiang Lin, Demetrios G. Vavvas May 2017

Atorvastatin Promotes Phagocytosis And Attenuates Pro-Inflammatory Response In Human Retinal Pigment Epithelial Cells, Bo Tian, Ahmad Al-Moujahed, Peggy Bouzika, Yijun Hu, Shoji Notomi, Pavlina Tsoka, Joan W. Miller, Haijiang Lin, Demetrios G. Vavvas

Open Access Articles

Phagocytosis of daily shed photoreceptor outer segments is an important function of the retinal pigment epithelium (RPE) and it is essential for retinal homeostasis. RPE dysfunction, especially impairment of its phagocytic ability, plays an essential role in the pathogenesis of age-related macular degeneration (AMD). Statins, or HMG CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, are drugs with multiple properties that have been extensively used to treat hyperlipidemia. However, their effect on RPE cells has not been fully elucidated. Here we report that high dose atorvastatin increased the phagocytic function of ARPE-19 cells, as well as rescue the cells from the phagocytic dysfunction ...


Characterization Of A New Oda3 Allele, Oda3-6, Defective In Assembly Of The Outer Dynein Arm-Docking Complex In Chlamydomonas Reinhardtii, Jason M. Brown, Matthew Mosley, Daniela Montes-Berrueta, Yuqing Hou, Fan Yang, Chasity Scarbrough, George B. Witman, Maureen Wirschell Mar 2017

Characterization Of A New Oda3 Allele, Oda3-6, Defective In Assembly Of The Outer Dynein Arm-Docking Complex In Chlamydomonas Reinhardtii, Jason M. Brown, Matthew Mosley, Daniela Montes-Berrueta, Yuqing Hou, Fan Yang, Chasity Scarbrough, George B. Witman, Maureen Wirschell

Open Access Articles

We have used an insertional mutagenesis approach to generate new C. reinhardtii motility mutants. Of 56 mutants isolated, one is a new allele at the ODA3 locus, called oda3-6. Similar to the previously characterized oda3 alleles, oda3-6 has a slow-jerky swimming phenotype and reduced swimming speed. The oda3-6 mutant fails to assemble the outer dynein arm motor and outer dynein arm-docking complex (ODA-DC) in the ciliary axoneme due to an insertion in the 5' end of the DCC1 gene, which encodes the DC1 subunit of the ODA-DC. Transformation of oda3-6 with the wild-type DCC1 gene rescues the mutant swimming phenotype ...


Distinct Kinase-Independent Role Of Ripk3 In Cd11c+ Mononuclear Phagocytes In Cytokine-Induced Tissue Repair, Kenta Moriwaki, Sakthi Balaji, John Bertin, Peter J. Gough, Francis Ka-Ming Chan Mar 2017

Distinct Kinase-Independent Role Of Ripk3 In Cd11c+ Mononuclear Phagocytes In Cytokine-Induced Tissue Repair, Kenta Moriwaki, Sakthi Balaji, John Bertin, Peter J. Gough, Francis Ka-Ming Chan

Open Access Articles

Receptor interacting protein kinase 3 (RIPK3) induces necroptosis, a type of regulated necrosis, through its kinase domain and receptor interacting protein (RIP) homotypic interaction motif (RHIM). In addition, RIPK3 has been shown to regulate NLRP3 inflammasome and nuclear factor kappaB (NF-kappaB) activation. However, the relative contribution of these signaling pathways to RIPK3-dependent inflammation in distinct immune effectors is unknown. To investigate these questions, we generated RIPK3-GFP reporter mice. We found that colonic CD11c+CD11b+CD14+ mononuclear phagocytes (MNPs) expressed the highest level of RIPK3 in the lamina propria. Consequently, deletion of the RIPK3 RHIM in CD11c+ cells alone was sufficient ...


Metformin Inhibits The Proliferation Of Benign Prostatic Epithelial Cells, Zongwei Wang, Xingyuan Xiao, Rongbin Ge, Jijun Li, Cameron W. Johnson, Cyrus Rassoulian, Aria F. Olumi Mar 2017

Metformin Inhibits The Proliferation Of Benign Prostatic Epithelial Cells, Zongwei Wang, Xingyuan Xiao, Rongbin Ge, Jijun Li, Cameron W. Johnson, Cyrus Rassoulian, Aria F. Olumi

Open Access Articles

OBJECTIVE: Benign prostatic hyperplasia (BPH) is the most common proliferative abnormality of the prostate affecting elderly men throughout the world. Epidemiologic studies have shown that diabetes significantly increases the risk of developing BPH, although whether anti-diabetic medications preventing the development of BPH remains to be defined. We have previously found that stromally expressed insulin-like growth factor 1 (IGF-1) promotes benign prostatic epithelial cell proliferation through paracrine mechanisms. Here, we seek to understand if metformin, a first line medication for the treatment of type 2 diabetes, inhibits the proliferation of benign prostatic epithelial cells through reducing the expression of IGF-1 receptor ...


Phosphorylation Of Cardiac Myosin Binding Protein C Releases Myosin Heads From The Surface Of Cardiac Thick Filaments, Robert W. Kensler, Roger Craig, Richard L. Moss Feb 2017

Phosphorylation Of Cardiac Myosin Binding Protein C Releases Myosin Heads From The Surface Of Cardiac Thick Filaments, Robert W. Kensler, Roger Craig, Richard L. Moss

Open Access Articles

Cardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the ...


Hlh-30/Tfeb-Mediated Autophagy Functions In A Cell-Autonomous Manner For Epithelium Intrinsic Cellular Defense Against Bacterial Pore-Forming Toxin In C. Elegans, Huan-Da Chen, Raffi V. Aroian, Chang-Shi Chen Feb 2017

Hlh-30/Tfeb-Mediated Autophagy Functions In A Cell-Autonomous Manner For Epithelium Intrinsic Cellular Defense Against Bacterial Pore-Forming Toxin In C. Elegans, Huan-Da Chen, Raffi V. Aroian, Chang-Shi Chen

Open Access Articles

Autophagy is an evolutionarily conserved intracellular system that maintains cellular homeostasis by degrading and recycling damaged cellular components. The transcription factor HLH-30/TFEB-mediated autophagy has been reported to regulate tolerance to bacterial infection, but less is known about the bona fide bacterial effector that activates HLH-30 and autophagy. Here, we reveal that bacterial membrane pore-forming toxin (PFT) induces autophagy in an HLH-30-dependent manner in Caenorhabditis elegans. Moreover, autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously in the PFT-targeted intestinal cells in C. elegans. These results demonstrate that autophagic pathways ...


Ror2 Signaling Regulates Golgi Structure And Transport Through Ift20 For Tumor Invasiveness, Michiru Nishita, Seung-Yeol Park, Tadashi Nishio, Koki Kamizaki, Zhichao Wang, Kota Tamada, Toru Takumi, Ryuju Hashimoto, Hiroki Otani, Gregory J. Pazour, Victor W. Hsu, Yasuhiro Minami Jan 2017

Ror2 Signaling Regulates Golgi Structure And Transport Through Ift20 For Tumor Invasiveness, Michiru Nishita, Seung-Yeol Park, Tadashi Nishio, Koki Kamizaki, Zhichao Wang, Kota Tamada, Toru Takumi, Ryuju Hashimoto, Hiroki Otani, Gregory J. Pazour, Victor W. Hsu, Yasuhiro Minami

Open Access Articles

Signaling through the Ror2 receptor tyrosine kinase promotes invadopodia formation for tumor invasion. Here, we identify intraflagellar transport 20 (IFT20) as a new target of this signaling in tumors that lack primary cilia, and find that IFT20 mediates the ability of Ror2 signaling to induce the invasiveness of these tumors. We also find that IFT20 regulates the nucleation of Golgi-derived microtubules by affecting the GM130-AKAP450 complex, which promotes Golgi ribbon formation in achieving polarized secretion for cell migration and invasion. Furthermore, IFT20 promotes the efficiency of transport through the Golgi complex. These findings shed new insights into how Ror2 signaling ...


The Trypanosome Exocyst: A Conserved Structure Revealing A New Role In Endocytosis, Cordula M. Boehm, Samson Obado, Catarina Gadelha, Alexandra Kaupisch, Paul T. Manna, Gwyn W. Gould, Mary Munson, Brian T. Chait, Michael P. Rout, Mark C. Field Jan 2017

The Trypanosome Exocyst: A Conserved Structure Revealing A New Role In Endocytosis, Cordula M. Boehm, Samson Obado, Catarina Gadelha, Alexandra Kaupisch, Paul T. Manna, Gwyn W. Gould, Mary Munson, Brian T. Chait, Michael P. Rout, Mark C. Field

Open Access Articles

Membrane transport is an essential component of pathogenesis for most infectious organisms. In African trypanosomes, transport to and from the plasma membrane is closely coupled to immune evasion and antigenic variation. In mammals and fungi an octameric exocyst complex mediates late steps in exocytosis, but comparative genomics suggested that trypanosomes retain only six canonical subunits, implying mechanistic divergence. We directly determined the composition of the Trypanosoma brucei exocyst by affinity isolation and demonstrate that the parasite complex is nonameric, retaining all eight canonical subunits (albeit highly divergent at the sequence level) plus a novel essential subunit, Exo99. Exo99 and Sec15 ...