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Full-Text Articles in Cell Biology

Bta-Mir-24-3p Controls The Myogenic Differentiation And Proliferation Of Fetal, Bovine, Skeletal Muscle-Derived Progenitor Cells By Targeting Acvr1b, Xin Hu, Yishen Xing, Ling Ren, Yahui Wang, Qian Li, Xing Fu, Qiyuan Yang, Lingyang Xu, Luc Willems, Junya Li, Lupei Zhang Oct 2019

Bta-Mir-24-3p Controls The Myogenic Differentiation And Proliferation Of Fetal, Bovine, Skeletal Muscle-Derived Progenitor Cells By Targeting Acvr1b, Xin Hu, Yishen Xing, Ling Ren, Yahui Wang, Qian Li, Xing Fu, Qiyuan Yang, Lingyang Xu, Luc Willems, Junya Li, Lupei Zhang

Open Access Articles

MicroRNAs modulate a variety of cellular events, including skeletal muscle development, but the molecular basis of their functions in fetal bovine skeletal muscle development is poorly understood. In this study, we report that bta-miR-24-3p promotes the myogenic differentiation of fetal bovine PDGFRalpha(-) progenitor cells. The expression of bta-miR-24-3p increased during myogenic differentiation. Overexpression of bta-miR-24-3p significantly promoted myogenic differentiation, but inhibited proliferation. A dual-luciferase assay identified ACVR1B as a direct target of bta-miR-24-3p. Similarly, knocking down ACVR1B by RNA interference also significantly inhibited proliferation and promoted the differentiation of bovine PDGFRalpha(-) progenitor cells. Thus, our study provides a mechanism in ...


Ripk1 Mediates Tnf-Induced Intestinal Crypt Apoptosis During Chronic Nf-Kappab Activation, Jerry Wong, Matija Zelic, John Bertin, Michelle A. Kelliher, Monica Guma Oct 2019

Ripk1 Mediates Tnf-Induced Intestinal Crypt Apoptosis During Chronic Nf-Kappab Activation, Jerry Wong, Matija Zelic, John Bertin, Michelle A. Kelliher, Monica Guma

Open Access Articles

BACKGROUND AND AIMS: Tumor necrosis factor (TNF) is a major pathogenic effector and a therapeutic target in inflammatory bowel disease (IBD), yet the basis for TNF-induced intestinal epithelial cell (IEC) death is unknown, because TNF does not kill normal IECs. Here, we investigated how chronic nuclear factor (NF)- kappaB activation, which occurs in human IBD, promotes TNF-dependent IEC death in mice.

METHODS: Human IBD specimens were stained for p65 and cleaved caspase-3. C57BL/6 mice with constitutively active IKKbeta in IEC (Ikkbeta(EE)(IEC)), Ripk1(D138N/D138N) knockin mice, and Ripk3(-/-) mice were injected with TNF or lipopolysaccharide. Enteroids were ...


Control Of Cellular Responses To Mechanical Cues Through Yap/Taz Regulation, Ishani Dasgupta, Dannel Mccollum Oct 2019

Control Of Cellular Responses To Mechanical Cues Through Yap/Taz Regulation, Ishani Dasgupta, Dannel Mccollum

Open Access Articles

To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, differentiation as well as the processes of tissue regeneration and wound repair (1). Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states such as fibrosis, muscle diseases ...


A Small Peptide Antagonist Of The Fas Receptor Inhibits Neuroinflammation And Prevents Axon Degeneration And Retinal Ganglion Cell Death In An Inducible Mouse Model Of Glaucoma, Anitha Krishnan, Andrew J. Kocab, David N. Zacks, Ann Marshak-Rothstein, Meredith Gregory-Ksander Sep 2019

A Small Peptide Antagonist Of The Fas Receptor Inhibits Neuroinflammation And Prevents Axon Degeneration And Retinal Ganglion Cell Death In An Inducible Mouse Model Of Glaucoma, Anitha Krishnan, Andrew J. Kocab, David N. Zacks, Ann Marshak-Rothstein, Meredith Gregory-Ksander

Open Access Articles

BACKGROUND: Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma.

METHODS: Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in ...


Distinct Transcriptional Roles For Histone H3-K56 Acetylation During The Cell Cycle In Yeast, Salih Topal, Pauline Vasseur, Marta Radman-Livaja, Craig L. Peterson Sep 2019

Distinct Transcriptional Roles For Histone H3-K56 Acetylation During The Cell Cycle In Yeast, Salih Topal, Pauline Vasseur, Marta Radman-Livaja, Craig L. Peterson

Open Access Articles

Dynamic disruption and reassembly of promoter-proximal nucleosomes is a conserved hallmark of transcriptionally active chromatin. Histone H3-K56 acetylation (H3K56Ac) enhances these turnover events and promotes nucleosome assembly during S phase. Here we sequence nascent transcripts to investigate the impact of H3K56Ac on transcription throughout the yeast cell cycle. We find that H3K56Ac is a genome-wide activator of transcription. While H3K56Ac has a major impact on transcription initiation, it also appears to promote elongation and/or termination. In contrast, H3K56Ac represses promiscuous transcription that occurs immediately following replication fork passage, in this case by promoting efficient nucleosome assembly. We also detect ...


Leptin Promotes Expression Of Emt-Related Transcription Factors And Invasion In A Src And Fak-Dependent Pathway In Mcf10a Mammary Epithelial Cells, Monserrat Olea-Flores, Miriam Zuniga-Eulogio, Arvey Tacuba-Saavedra, Magdalena Bueno-Salgado, Andrea Sanchez-Carvajal, Yovani Vargas-Santiago, Miguel A. Mendoza-Catalan, Eduardo Perez Salazar, Alejandra Garcia-Hernandez, Teresita Padilla-Benavides, Napoleon Navarro-Tito Sep 2019

Leptin Promotes Expression Of Emt-Related Transcription Factors And Invasion In A Src And Fak-Dependent Pathway In Mcf10a Mammary Epithelial Cells, Monserrat Olea-Flores, Miriam Zuniga-Eulogio, Arvey Tacuba-Saavedra, Magdalena Bueno-Salgado, Andrea Sanchez-Carvajal, Yovani Vargas-Santiago, Miguel A. Mendoza-Catalan, Eduardo Perez Salazar, Alejandra Garcia-Hernandez, Teresita Padilla-Benavides, Napoleon Navarro-Tito

Open Access Articles

Leptin is one of the main adipokines secreted in breast tissue. Leptin promotes epithelial-mesenchymal transition (EMT), cell migration and invasion in epithelial breast cells, leading to tumor progression. Although, the molecular mechanisms that underlie these events are not fully understood, the activation of different signaling pathways appears to be essential. In this sense, the effects of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, are not completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A ...


A Critical Role Of Vmp1 In Lipoprotein Secretion, Hideaki Morishita, Yan G. Zhao, Norito Tamura, Taki Nishimura, Yuki Kanda, Yuriko Sakamaki, Mitsuyo Okazaki, Dongfang Li, Noboru Mizushima Sep 2019

A Critical Role Of Vmp1 In Lipoprotein Secretion, Hideaki Morishita, Yan G. Zhao, Norito Tamura, Taki Nishimura, Yuki Kanda, Yuriko Sakamaki, Mitsuyo Okazaki, Dongfang Li, Noboru Mizushima

Open Access Articles

Lipoproteins are lipid-protein complexes that are primarily generated and secreted from the intestine, liver, and visceral endoderm and delivered to peripheral tissues. Lipoproteins, which are assembled in the endoplasmic reticulum (ER) membrane, are released into the ER lumen for secretion, but its mechanism remains largely unknown. Here, we show that the release of lipoproteins from the ER membrane requires VMP1, an ER transmembrane protein essential for autophagy and certain types of secretion. Loss of vmp1, but not other autophagy-related genes, in zebrafish causes lipoprotein accumulation in the intestine and liver. Vmp1 deficiency in mice also leads to lipid accumulation in ...


Extensive Ribosome And Rf2 Rearrangements During Translation Termination, Egor Svidritskiy, Gabriel Demo, Anna B. Loveland, Chen Xu, Andrei A. Korostelev Sep 2019

Extensive Ribosome And Rf2 Rearrangements During Translation Termination, Egor Svidritskiy, Gabriel Demo, Anna B. Loveland, Chen Xu, Andrei A. Korostelev

Open Access Articles

Protein synthesis ends when a ribosome reaches an mRNA stop codon. Release factors (RFs) decode the stop codon, hydrolyze peptidyl-tRNA to release the nascent protein, and then dissociate to allow ribosome recycling. To visualize termination by RF2, we resolved a cryo-EM ensemble of E. coli 70S*RF2 structures at up to 3.3 A in a single sample. Five structures suggest a highly dynamic termination pathway. Upon peptidyl-tRNA hydrolysis, the CCA end of deacyl-tRNA departs from the peptidyl transferase center. The catalytic GGQ loop of RF2 is rearranged into a long beta-hairpin that plugs the peptide tunnel, biasing a nascent ...


Diverse Repertoire Of Human Adipocyte Subtypes Develops From Transcriptionally Distinct Mesenchymal Progenitor Cells, So Yun Min, Anand Desai, Zinger Yang, Agastya Sharma, Tiffany Desouza, Ryan Genga, Alper Kucukural, Lawrence M. Lifshitz, Soren Nielsen, Camilla Scheele, Rene Maehr, Manuel Garber, Silvia Corvera Sep 2019

Diverse Repertoire Of Human Adipocyte Subtypes Develops From Transcriptionally Distinct Mesenchymal Progenitor Cells, So Yun Min, Anand Desai, Zinger Yang, Agastya Sharma, Tiffany Desouza, Ryan Genga, Alper Kucukural, Lawrence M. Lifshitz, Soren Nielsen, Camilla Scheele, Rene Maehr, Manuel Garber, Silvia Corvera

Open Access Articles

Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of "brite/beige" thermogenic adipocytes reveals mechanisms for ...


Atf6alpha Impacts Cell Number By Influencing Survival, Death And Proliferation, Rohit B. Sharma, Jarin T. Snyder, Laura C. Alonso Sep 2019

Atf6alpha Impacts Cell Number By Influencing Survival, Death And Proliferation, Rohit B. Sharma, Jarin T. Snyder, Laura C. Alonso

Open Access Articles

BACKGROUND: A growing body of literature suggests the cell-intrinsic activity of Atf6alpha during ER stress responses has implications for tissue cell number during growth and development, as well as in adult biology and tumorigenesis [1]. This concept is important, linking the cellular processes of secretory protein synthesis and endoplasmic reticulum stress response with functional tissue capacity and organ size. However, the field contains conflicting observations, especially notable in secretory cell types like the pancreatic beta cell.

SCOPE OF REVIEW: Here we summarize current knowledge of the basic biology of Atf6alpha, along with the pleiotropic roles Atf6alpha plays in cell life ...


Role Of A 19s Proteasome Subunit- Psmd10(Gankyrin) In Neurogenesis Of Human Neuronal Progenitor Cells, Indrajit Sahu, Padma P. Nanaware, Minal Mane, Saim Wasi Mulla, Soumen Roy, Prasanna Venkatraman Aug 2019

Role Of A 19s Proteasome Subunit- Psmd10(Gankyrin) In Neurogenesis Of Human Neuronal Progenitor Cells, Indrajit Sahu, Padma P. Nanaware, Minal Mane, Saim Wasi Mulla, Soumen Roy, Prasanna Venkatraman

Open Access Articles

PSMD10(Gankyrin), a proteasome assembly chaperone, is a widely known oncoprotein which aspects many hall mark properties of cancer. However, except proteasome assembly chaperon function its role in normal cell function remains unknown. To address this issue, we induced PSMD10(Gankyrin) overexpression in HEK293 cells and the resultant large-scale changes in gene expression profile were analyzed. We constituted networks from microarray data of these differentially expressed genes and carried out extensive topological analyses. The overrecurring yet consistent theme that appeared throughout analysis using varied network metrics is that all genes and interactions identified as important would be involved in neurogenesis ...


Promotion Of Adipogenesis By Jmjd6 Requires The At Hook-Like Domain And Is Independent Of Its Catalytic Function, Pablo Reyes-Gutierrez, Jake W. Carrasquillo-Rodriguez, Anthony N. Imbalzano Aug 2019

Promotion Of Adipogenesis By Jmjd6 Requires The At Hook-Like Domain And Is Independent Of Its Catalytic Function, Pablo Reyes-Gutierrez, Jake W. Carrasquillo-Rodriguez, Anthony N. Imbalzano

Open Access Articles

JMJD6 is a member of the Jumonji C domain containing enzymes that demethylate and/or hydroxylate substrate proteins. It is a multi-functional protein that has been implicated in disparate aspects of transcriptional and post-transcriptional control of gene expression, including but not limited to enhancer and promoter binding, release of paused RNA polymerase II, control of splicing, and interaction with the translation machinery. JMJD6 contributes to multiple aspects of animal development, including adipogenesis modeled in culture. We mutated proposed or characterized domains in the JMJD6 protein to better understand the requirement for JMJD6 in adipogenic differentiation. Mutation of JMJD6 amino acids ...


Calcineurin Broadly Regulates The Initiation Of Skeletal Muscle-Specific Gene Expression By Binding Target Promoters And Facilitating The Interaction Of The Swi/Snf Chromatin Remodeling Enzyme, Hanna Witwicka, Jumpei Nogami, Sabriya A. Syed, Kazumitsu Maehara, Teresita Padilla-Benavides, Yasuyuki Ohkawa, Anthony N. Imbalzano Jul 2019

Calcineurin Broadly Regulates The Initiation Of Skeletal Muscle-Specific Gene Expression By Binding Target Promoters And Facilitating The Interaction Of The Swi/Snf Chromatin Remodeling Enzyme, Hanna Witwicka, Jumpei Nogami, Sabriya A. Syed, Kazumitsu Maehara, Teresita Padilla-Benavides, Yasuyuki Ohkawa, Anthony N. Imbalzano

Open Access Articles

Calcineurin (Cn) is a calcium-activated serine/threonine protein phosphatase that is broadly implicated in diverse cellular processes, including the regulation of gene expression. During skeletal muscle differentiation, Cn activates the NFAT transcription factor but also promotes differentiation by counteracting the negative influences of protein kinase C beta (PKCbeta) via dephosphorylation and activation of BRG1, an enzymatic subunit of the mammalian SWI/SNF ATP-dependent chromatin remodeling enzyme. Here we identified four major temporal patterns of Cn-dependent gene expression in differentiating myoblasts and determined that Cn is broadly required for the activation of the myogenic gene expression program. Mechanistically, Cn promotes gene ...


F-Box Protein Fbxo16 Functions As A Tumor Suppressor By Attenuating Nuclear Beta-Catenin Function, Debasish Paul, Sehbanul Islam, Rajesh Kumar. Manne, U. S. Dinesh, Sunil K. Malonia, Biswanath Maity, Ramanamurthy Boppana, Srikanth Rapole, Praveen Kumar Shetty, Manas Kumar Santra Jul 2019

F-Box Protein Fbxo16 Functions As A Tumor Suppressor By Attenuating Nuclear Beta-Catenin Function, Debasish Paul, Sehbanul Islam, Rajesh Kumar. Manne, U. S. Dinesh, Sunil K. Malonia, Biswanath Maity, Ramanamurthy Boppana, Srikanth Rapole, Praveen Kumar Shetty, Manas Kumar Santra

Open Access Articles

Aberrant activation of beta-catenin has been implicated in a variety of human diseases, including cancer. In spite of significant progress, the regulation of active Wnt/beta-catenin-signaling pathways is still poorly understood. In this study, we show that F-box protein 16 (FBXO16) is a putative tumor suppressor. It is a component of the SCF (SKP1-Cullin1-F-box protein) complex, which targets the nuclear beta-catenin protein to facilitate proteasomal degradation through the 26S proteasome. FBXO16 interacts physically with the C-terminal domain of beta-catenin and promotes its lysine 48-linked polyubiquitination. In addition, it inhibits epithelial-to-mesenchymal transition (EMT) by attenuating the level of beta-catenin. Therefore, depletion ...


Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial-Mesenchymal Transition In Cancer, Monserrat Olea-Flores, Miriam Daniela Zuniga-Eulogio, Miguel Angel Mendoza-Catalan, Hugo Alberto Rodriguez-Ruiz, Eduardo Castaneda-Saucedo, Carlos Ortuno-Pineda, Teresita Padilla-Benavides, Napoleon Navarro-Tito Jun 2019

Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial-Mesenchymal Transition In Cancer, Monserrat Olea-Flores, Miriam Daniela Zuniga-Eulogio, Miguel Angel Mendoza-Catalan, Hugo Alberto Rodriguez-Ruiz, Eduardo Castaneda-Saucedo, Carlos Ortuno-Pineda, Teresita Padilla-Benavides, Napoleon Navarro-Tito

Open Access Articles

Epithelial-mesenchymal transition (EMT) is a reversible cellular process, characterized by changes in gene expression and activation of proteins, favoring the trans-differentiation of the epithelial phenotype to a mesenchymal phenotype. This process increases cell migration and invasion of tumor cells, progression of the cell cycle, and resistance to apoptosis and chemotherapy, all of which support tumor progression. One of the signaling pathways involved in tumor progression is the MAPK pathway. Within this family, the ERK subfamily of proteins is known for its contributions to EMT. The ERK subfamily is divided into typical (ERK 1/2/5), and atypical (ERK 3/4 ...


Adipocyte Acly Facilitates Dietary Carbohydrate Handling To Maintain Metabolic Homeostasis In Females, Sully Fernandez, John M. Viola, Annmarie Torres, Martina Wallace, Sophie Trefely, Steven Zhao, Hayley C. Affronti, Jivani M. Gengatharan, David A. Guertin, Nathaniel W. Snyder, Christian M. Metallo, Kathryn E. Wellen May 2019

Adipocyte Acly Facilitates Dietary Carbohydrate Handling To Maintain Metabolic Homeostasis In Females, Sully Fernandez, John M. Viola, Annmarie Torres, Martina Wallace, Sophie Trefely, Steven Zhao, Hayley C. Affronti, Jivani M. Gengatharan, David A. Guertin, Nathaniel W. Snyder, Christian M. Metallo, Kathryn E. Wellen

Open Access Articles

Sugars and refined carbohydrates are major components of the modern diet. ATP-citrate lyase (ACLY) is upregulated in adipocytes in response to carbohydrate consumption and generates acetyl-coenzyme A (CoA) for both lipid synthesis and acetylation reactions. Here, we investigate the role of ACLY in the metabolic and transcriptional responses to carbohydrates in adipocytes and unexpectedly uncover a sexually dimorphic function in maintaining systemic metabolic homeostasis. When fed a high-sucrose diet, Acly(FAT-/-) females exhibit a lipodystrophy-like phenotype, with minimal fat accumulation, insulin resistance, and hepatic lipid accumulation, whereas Acly(FAT-/-) males have only mild metabolic phenotypes. We find that ACLY is ...


Serum Deprivation Of Mesenchymal Stem Cells Improves Exosome Activity And Alters Lipid And Protein Composition, Reka A. Haraszti, Rachael Miller, Michelle L. Dubuke, Andrew H. Coles, Marie C. Didiot, Dimas Echeverria, Matteo Stoppato, Yves Y. Sere, John D. Leszyk, Julia F. Alterman, Bruno M. D. C. Godinho, Matthew R. Hassler, Rachel Wollacott, Yan Wang, Scott A. Shaffer, Neil Aronin, Anastasia Khvorova May 2019

Serum Deprivation Of Mesenchymal Stem Cells Improves Exosome Activity And Alters Lipid And Protein Composition, Reka A. Haraszti, Rachael Miller, Michelle L. Dubuke, Andrew H. Coles, Marie C. Didiot, Dimas Echeverria, Matteo Stoppato, Yves Y. Sere, John D. Leszyk, Julia F. Alterman, Bruno M. D. C. Godinho, Matthew R. Hassler, Rachel Wollacott, Yan Wang, Scott A. Shaffer, Neil Aronin, Anastasia Khvorova

Open Access Articles

Exosomes can serve as delivery vehicles for advanced therapeutics. The components necessary and sufficient to support exosomal delivery have not been established. Here we connect biochemical composition and activity of exosomes to optimize exosome-mediated delivery of small interfering RNAs (siRNAs). This information is used to create effective artificial exosomes. We show that serum-deprived mesenchymal stem cells produce exosomes up to 22-fold more effective at delivering siRNAs to neurons than exosomes derived from control cells. Proteinase treatment of exosomes stops siRNA transfer, indicating that surface proteins on exosomes are involved in trafficking. Proteomic and lipidomic analyses show that exosomes derived in ...


Single-Cell Rna-Sequencing-Based Crispri Screening Resolves Molecular Drivers Of Early Human Endoderm Development, Ryan M. Genga, Eric M. Kernfeld, Krishna M. Parsi, Teagan J. Parsons, Michael J. Ziller, Rene Maehr Apr 2019

Single-Cell Rna-Sequencing-Based Crispri Screening Resolves Molecular Drivers Of Early Human Endoderm Development, Ryan M. Genga, Eric M. Kernfeld, Krishna M. Parsi, Teagan J. Parsons, Michael J. Ziller, Rene Maehr

Open Access Articles

Studies in vertebrates have outlined conserved molecular control of definitive endoderm (END) development. However, recent work also shows that key molecular aspects of human END regulation differ even from rodents. Differentiation of human embryonic stem cells (ESCs) to END offers a tractable system to study the molecular basis of normal and defective human-specific END development. Here, we interrogated dynamics in chromatin accessibility during differentiation of ESCs to END, predicting DNA-binding proteins that may drive this cell fate transition. We then combined single-cell RNA-seq with parallel CRISPR perturbations to comprehensively define the loss-of-function phenotype of those factors in END development. Following ...


The Erk Mapk Pathway Is Essential For Skeletal Development And Homeostasis, Jung-Min Kim, Yeon-Suk Yang, Kwang Hwan Park, Hwanhee Oh, Matthew B. Greenblatt, Jae-Hyuck Shim Apr 2019

The Erk Mapk Pathway Is Essential For Skeletal Development And Homeostasis, Jung-Min Kim, Yeon-Suk Yang, Kwang Hwan Park, Hwanhee Oh, Matthew B. Greenblatt, Jae-Hyuck Shim

Open Access Articles

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1(Osx)Mek2(-/-)), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans ...


The Er-Localized Protein Dfcp1 Modulates Er-Lipid Droplet Contact Formation, Dongfang Li, Yan G. Zhao, Di Li, Hongyu Zhao, Jie Huang, Guangyan Miao, Du Feng, Pingsheng Liu, Dong Li, Hong Zhang Apr 2019

The Er-Localized Protein Dfcp1 Modulates Er-Lipid Droplet Contact Formation, Dongfang Li, Yan G. Zhao, Di Li, Hongyu Zhao, Jie Huang, Guangyan Miao, Du Feng, Pingsheng Liu, Dong Li, Hong Zhang

Open Access Articles

Very little is known about the spatiotemporal generation of lipid droplets (LDs) from the endoplasmic reticulum (ER) and the factors that mediate ER-LD contacts for LD growth. Using super-resolution grazing incidence structured illumination microscopy (GI-SIM) live-cell imaging, we reveal that upon LD induction, the ER-localized protein DFCP1 redistributes to nascent puncta on the ER, whose formation depends on triglyceride synthesis. These structures move along the ER and fuse to form expanding LDs. Fusion and expansion of DFCP1-labeled nascent structures is controlled by BSCL2. BSCL2 depletion causes accumulation of nascent DFCP1 structures. DFCP1 overexpression increases LD size and enhances ER-LD contacts ...


Transfer Rna Genes Affect Chromosome Structure And Function Via Local Effects, Omar Hamdani, Tsung-Han S. Hsieh, Oliver J. Rando, Rohinton T. Kamakaka Apr 2019

Transfer Rna Genes Affect Chromosome Structure And Function Via Local Effects, Omar Hamdani, Tsung-Han S. Hsieh, Oliver J. Rando, Rohinton T. Kamakaka

Open Access Articles

The genome is packaged and organized in an ordered, non-random manner and specific chromatin segments contact nuclear substructures to mediate this organization. Transfer RNA genes (tDNAs) are binding sites for transcription factors and architectural proteins and are thought to play an important role in the organization of the genome. In this study, we investigate the role of tDNAs in genomic organization and chromosome function by editing a chromosome so that it lacks any tDNAs. Surprisingly our analyses of this tDNA-less chromosome show that loss of tDNAs does not grossly affect chromatin architecture or chromosome tethering and mobility. However, loss of ...


Adenosine Triphosphate Is Co-Secreted With Glucagon-Like Peptide-1 To Modulate Intestinal Enterocytes And Afferent Neurons, Van B. Lu, Juraj Rievaj, Elisabeth A. O'Flaherty, Christopher A. Smith, Ramona Pais, Luke A. Pattison, Gwen Tolhurst, Andrew B. Leiter, David C. Bulmer, Fiona M. Gribble, Frank Reimann Mar 2019

Adenosine Triphosphate Is Co-Secreted With Glucagon-Like Peptide-1 To Modulate Intestinal Enterocytes And Afferent Neurons, Van B. Lu, Juraj Rievaj, Elisabeth A. O'Flaherty, Christopher A. Smith, Ramona Pais, Luke A. Pattison, Gwen Tolhurst, Andrew B. Leiter, David C. Bulmer, Fiona M. Gribble, Frank Reimann

Open Access Articles

Enteroendocrine cells are specialised sensory cells located in the intestinal epithelium and generate signals in response to food ingestion. Whilst traditionally considered hormone-producing cells, there is evidence that they also initiate activity in the afferent vagus nerve and thereby signal directly to the brainstem. We investigate whether enteroendocrine L-cells, well known for their production of the incretin hormone glucagon-like peptide-1 (GLP-1), also release other neuro-transmitters/modulators. We demonstrate regulated ATP release by ATP measurements in cell supernatants and by using sniffer patches that generate electrical currents upon ATP exposure. Employing purinergic receptor antagonists, we demonstrate that evoked ATP release from ...


Receptor Interacting Protein Kinase 3 (Rip3) Regulates Ipscs Generation Through Modulating Cell Cycle Progression Genes, Ahmad Al-Moujahed, Bo Tian, Nikolaos E. Efstathiou, Eleni K. Konstantinou, Mien Hoang, Haijiang Lin, Joan W. Miller, Demetrios G. Vavvas Mar 2019

Receptor Interacting Protein Kinase 3 (Rip3) Regulates Ipscs Generation Through Modulating Cell Cycle Progression Genes, Ahmad Al-Moujahed, Bo Tian, Nikolaos E. Efstathiou, Eleni K. Konstantinou, Mien Hoang, Haijiang Lin, Joan W. Miller, Demetrios G. Vavvas

Open Access Articles

The molecular mechanisms involved in induced pluripotent stem cells (iPSCs) generation are poorly understood. The cell death machinery of apoptosis-inducing caspases have been shown to facilitate the process of iPSCs reprogramming. However, the effect of other cell death processes, such as programmed necrosis (necroptosis), on iPSCs induction has not been studied. In this study, we investigated the role of receptor-interacting protein kinase 3 (RIP3), an essential regulator of necroptosis, in reprogramming mouse embryonic fibroblast cells (MEFs) into iPSCs. RIP3 was found to be upregulated in iPSCs compared to MEFs. Deletion of RIP3 dramatically suppressed the reprogramming of iPSCs (~82%). RNA-seq ...


Viral Infection Or Ifn-Alpha Alters Mitotic Spindle Orientation By Modulating Pericentrin Levels, William M. Mcdougall, Jill Perreira, Hui-Fang Hung, Anastassiia Vertii, E. Xiaofei, Wendy Zimmerman, Timothy F. Kowalik, Stephen J. Doxsey, Abraham L. Brass Feb 2019

Viral Infection Or Ifn-Alpha Alters Mitotic Spindle Orientation By Modulating Pericentrin Levels, William M. Mcdougall, Jill Perreira, Hui-Fang Hung, Anastassiia Vertii, E. Xiaofei, Wendy Zimmerman, Timothy F. Kowalik, Stephen J. Doxsey, Abraham L. Brass

Open Access Articles

Congenital microcephaly occurs in utero during Zika virus (ZIKV) infection. The single-gene disorder, Majewski osteodysplastic primordial dwarfism type II (MOPDII), also leads to microcephaly and is concomitant with a decrease in the centrosomal protein, pericentrin (PCNT). This protein is a known contributor of mitotic spindle misorientation and ultimately, microcephaly. Similar to MOPDII, either viral infection or interferon (IFN)-alpha exposure reduced PCNT levels at the mitotic spindle poles. We unexpectedly found that infection of cells with any one of a diverse set of viruses, such as ZIKV, dengue virus, cytomegalovirus, influenza A virus, or hepatitis B virus, or treatment of ...


Huntingtin Associates With The Actin Cytoskeleton And Alpha-Actinin Isoforms To Influence Stimulus Dependent Morphology Changes, Adelaide Tousley, Maria Iuliano, Elizabeth Weisman, Ellen Sapp, Heather Richardson, Petr Vodicka, Jonathan Alexander, Neil Aronin, Marian Difiglia, Kimberly B. Kegel-Gleason Feb 2019

Huntingtin Associates With The Actin Cytoskeleton And Alpha-Actinin Isoforms To Influence Stimulus Dependent Morphology Changes, Adelaide Tousley, Maria Iuliano, Elizabeth Weisman, Ellen Sapp, Heather Richardson, Petr Vodicka, Jonathan Alexander, Neil Aronin, Marian Difiglia, Kimberly B. Kegel-Gleason

Open Access Articles

One response of cells to growth factor stimulus involves changes in morphology driven by the actin cytoskeleton and actin associated proteins which regulate functions such as cell adhesion, motility and in neurons, synaptic plasticity. Previous studies suggest that Huntingtin may be involved in regulating morphology however, there has been limited evidence linking endogenous Huntingtin localization or function with cytoplasmic actin in cells. We found that depletion of Huntingtin in human fibroblasts reduced adhesion and altered morphology and these phenotypes were made worse with growth factor stimulation, whereas the presence of the Huntington's Disease mutation inhibited growth factor induced changes ...


Hypomorphic Mutations Of Trip11 Cause Odontochondrodysplasia, Anika Wehrle, John A. Follit, Gregory J. Pazour, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch Feb 2019

Hypomorphic Mutations Of Trip11 Cause Odontochondrodysplasia, Anika Wehrle, John A. Follit, Gregory J. Pazour, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch

Open Access Articles

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism ...


Vegf/Neuropilin Signaling In Cancer Stem Cells, Arthur M. Mercurio Jan 2019

Vegf/Neuropilin Signaling In Cancer Stem Cells, Arthur M. Mercurio

Open Access Articles

The function of vascular endothelial growth factor (VEGF) in cancer extends beyond angiogenesis and vascular permeability. Specifically, VEGF-mediated signaling occurs in tumor cells and this signaling contributes to key aspects of tumorigenesis including the self-renewal and survival of cancer stem cells (CSCs). In addition to VEGF receptor tyrosine kinases, the neuropilins (NRPs) are critical for mediating the effects of VEGF on CSCs, primarily because of their ability to impact the function of growth factor receptors and integrins. VEGF/NRP signaling can regulate the expression and function of key molecules that have been implicated in CSC function including Rho family guanosine ...


Hla-Do Modulates The Diversity Of The Mhc-Ii Self-Peptidome, Padma P. Nanaware, Mollie M. Jurewicz, John D. Leszyk, Scott A. Shaffer, Lawrence J. Stern Dec 2018

Hla-Do Modulates The Diversity Of The Mhc-Ii Self-Peptidome, Padma P. Nanaware, Mollie M. Jurewicz, John D. Leszyk, Scott A. Shaffer, Lawrence J. Stern

Open Access Articles

Presentation of antigenic peptides on MHC-II molecules is essential for tolerance to self and for initiation of immune responses against foreign antigens. DO (HLA-DO in humans, H2-O in mice) is a non-classical MHC-II protein that has been implicated in control of autoimmunity and regulation of neutralizing antibody responses to viruses. These effects likely are related to a role of DO in selecting MHC-II epitopes, but previous studies examining the effect of DO on presentation of selected CD4 T cell epitopes have been contradictory. To understand how DO modulates MHC-II antigen presentation, we characterized the full spectrum of peptides presented by ...


Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong Nov 2018

Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong

Open Access Articles

Glycosylation is a fundamental modification of proteins and membrane lipids. Toxins that utilize glycans as their receptors have served as powerful tools to identify key players in glycosylation processes. Here, we carried out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-mediated genome-wide loss-of-function screens using two related bacterial toxins, Shiga-like toxins (Stxs) 1 and 2, which use a specific glycolipid, globotriaosylceramide (Gb3), as receptors, and the plant toxin ricin, which recognizes a broad range of glycans. The Stxs screens identified major glycosyltransferases (GTs) and transporters involved in Gb3 biosynthesis, while the ricin screen identified GTs and transporters involved in N-linked ...


Colorectal Cancer Liver Metastatic Growth Depends On Pad4-Driven Citrullination Of The Extracellular Matrix, A. E. Yuzhalin, A. N. Gordon-Weeks, M. L. Tognoli, K. Jones, B. Markelc, R. Konietzny, R. Fischer, Aaron Muth, E. O'Neill, Paul R. Thompson, P. J. Venables, B. M. Kessler, S. Y. Lim, R. J. Muschel Nov 2018

Colorectal Cancer Liver Metastatic Growth Depends On Pad4-Driven Citrullination Of The Extracellular Matrix, A. E. Yuzhalin, A. N. Gordon-Weeks, M. L. Tognoli, K. Jones, B. Markelc, R. Konietzny, R. Fischer, Aaron Muth, E. O'Neill, Paul R. Thompson, P. J. Venables, B. M. Kessler, S. Y. Lim, R. J. Muschel

Open Access Articles

Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix ...