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Articles 151 - 180 of 235

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Tox Regulates Growth, Dna Repair, And Genomic Instability In T-Cell Acute Lymphoblastic Leukemia, Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Marina Theodorou, Jessica S. Blackburn, Brian J. Abraham, Yuka Namiki, Marc Mansour, Nouran S. Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon De Waard, Esha Jain, Myriam Boukhali, Mattia Lion, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B. Silverman, Ruslan I. Sadreyev, John M. Asara, Marjorie A. Oettinger, Wilhelm Haas, A. Thomas Look, Richard A. Young, Raul Mostoslavsky, Graham Dellaire, David M. Langenau Nov 2017

Tox Regulates Growth, Dna Repair, And Genomic Instability In T-Cell Acute Lymphoblastic Leukemia, Riadh Lobbardi, Jordan Pinder, Barbara Martinez-Pastor, Marina Theodorou, Jessica S. Blackburn, Brian J. Abraham, Yuka Namiki, Marc Mansour, Nouran S. Abdelfattah, Aleksey Molodtsov, Gabriela Alexe, Debra Toiber, Manon De Waard, Esha Jain, Myriam Boukhali, Mattia Lion, Deepak Bhere, Khalid Shah, Alejandro Gutierrez, Kimberly Stegmaier, Lewis B. Silverman, Ruslan I. Sadreyev, John M. Asara, Marjorie A. Oettinger, Wilhelm Haas, A. Thomas Look, Richard A. Young, Raul Mostoslavsky, Graham Dellaire, David M. Langenau

Molecular and Cellular Biochemistry Faculty Publications

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. …

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Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie Oct 2017

Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie

Molecular and Cellular Biochemistry Faculty Publications

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard molecular cloning …

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The Activity Of The Serotonin Receptor 2c Is Regulated By Alternative Splicing, Stefan Stamm, Samuel B. Gruber, Alexander G. Rabchevsky, Ronald B. Emeson Sep 2017

The Activity Of The Serotonin Receptor 2c Is Regulated By Alternative Splicing, Stefan Stamm, Samuel B. Gruber, Alexander G. Rabchevsky, Ronald B. Emeson

Molecular and Cellular Biochemistry Faculty Publications

The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos. Most 5HT2C isoforms show constitutive activity, i.e., signal without ligand binding. The constitutive activity of 5HT2C is …

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Progressive Age-Dependence And Frequency Difference In The Effect Of Gap Junctions On Active Cochlear Amplification And Hearing, Liang Zong, Jin Chen, Yan Zhu, Hong-Bo Zhao Jul 2017

Progressive Age-Dependence And Frequency Difference In The Effect Of Gap Junctions On Active Cochlear Amplification And Hearing, Liang Zong, Jin Chen, Yan Zhu, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

Mutations of Connexin 26 (Cx26, GJB2), which is a predominant gap junction isoform in the cochlea, can induce high incidence of nonsyndromic hearing loss. We previously found that targeted-deletion of Cx26 in supporting Deiters cells and outer pillar cells in the cochlea can influence outer hair cell (OHC) electromotility and reduce active cochlear amplification leading to hearing loss, even though there are no gap junction connexin expressions in the auditory sensory hair cells. Here, we further report that hearing loss and the reduction of active amplification in the Cx26 targeted-deletion mice are progressive and different at high and low …

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Chloroformate Derivatization For Tracing The Fate Of Amino Acids In Cells And Tissues By Multiple Stable Isotope Resolved Metabolomics (Msirm), Ye Yang, Teresa W. -M. Fan, Andrew N. Lane, Richard M. Higashi Jul 2017

Chloroformate Derivatization For Tracing The Fate Of Amino Acids In Cells And Tissues By Multiple Stable Isotope Resolved Metabolomics (Msirm), Ye Yang, Teresa W. -M. Fan, Andrew N. Lane, Richard M. Higashi

Center for Environmental and Systems Biochemistry Faculty Publications

Amino acids have crucial roles in central metabolism, both anabolic and catabolic. To elucidate these roles, steady-state concentrations of amino acids alone are insufficient, as each amino acid participates in multiple pathways and functions in a complex network, which can also be compartmentalized. Stable Isotope-Resolved Metabolomics (SIRM) is an approach that uses atom-resolved tracking of metabolites through biochemical transformations in cells, tissues, or whole organisms. Using different elemental stable isotopes to label multiple metabolite precursors makes it possible to resolve simultaneously the utilization of these precursors in a single experiment. Conversely, a single precursor labeled with two (or more) different …

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Recombinant Listeria Adhesion Protein Expressing Probiotics Protect Against Listeria Monocytogenes Infection In Animal Models, Valerie E. Ryan Dec 2016

Recombinant Listeria Adhesion Protein Expressing Probiotics Protect Against Listeria Monocytogenes Infection In Animal Models, Valerie E. Ryan

Open Access Theses

Listeria monocytogenes (Lm) is a foodborne pathogen, found ubiquitously in nature, and has a high morbidity rate among immunocompromised individuals, the elderly, and especially pregnant women and their fetuses resulting in abortion, stillbirth, and neonatal infection. There are currently no preventative medical interventions against Lm infection. The Listeria adhesion protein (LAP) is present in both pathogenic and non-pathogenic Listeria (i.e., L. innocua) and has shown to interact with host epithelial proteins causing tight junction dysregulation aiding in pathogen attachment and paracellular translocation across the host intestinal epithelium. Our lab has demonstrated that recombinant probiotics, Lactobacillus casei (LbcWT) expressing LAP …

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Respective Contributions Of Single And Compound Granule Fusion To Secretion By Activated Platelets, Anita Eckly, Jean-Yves Rinckel, Fabienne Proamer, Neslihan Ulas, Smita Joshi, Sidney W. Whiteheart, Christian Gachet Nov 2016

Respective Contributions Of Single And Compound Granule Fusion To Secretion By Activated Platelets, Anita Eckly, Jean-Yves Rinckel, Fabienne Proamer, Neslihan Ulas, Smita Joshi, Sidney W. Whiteheart, Christian Gachet

Molecular and Cellular Biochemistry Faculty Publications

Although granule secretion is pivotal in many platelet responses, the fusion routes of α and δ granule release remain uncertain. We used a 3D reconstruction approach based on electron microscopy to visualize the spatial organization of granules in unstimulated and activated platelets. Two modes of exocytosis were identified: a single mode that leads to release of the contents of individual granules and a compound mode that leads to the formation of granule-to-granule fusion, resulting in the formation of large multigranular compartments. Both modes occur during the course of platelet secretion. Single fusion events are more visible at lower levels of …

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Pleckstrin Homology (Ph) Domain Leucine-Rich Repeat Protein Phosphatase Controls Cell Polarity By Negatively Regulating The Activity Of Atypical Protein Kinase C, Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao Oct 2016

Pleckstrin Homology (Ph) Domain Leucine-Rich Repeat Protein Phosphatase Controls Cell Polarity By Negatively Regulating The Activity Of Atypical Protein Kinase C, Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao

Markey Cancer Center Faculty Publications

The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures …

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Lipophosphoglycans From Leishmania Amazonensis Strains Display Immunomodulatory Properties Via Tlr4 And Do Not Affect Sand Fly Infection, Paula M. Nogueira, Rafael R. Assis, Ana C. Torrecilhas, Elvira M. Saraiva, Natália L. Pessoa, Marco A. Campos, Eric F. Marialva, Cláudia M. Ríos-Velasquez, Felipe A. Pessoa, Nágila F. Secundino, Jerônimo N. Rugani, Elsa Nieves, Salvatore J. Turco, Maria N. Melo, Rodrigo P. Soares Aug 2016

Lipophosphoglycans From Leishmania Amazonensis Strains Display Immunomodulatory Properties Via Tlr4 And Do Not Affect Sand Fly Infection, Paula M. Nogueira, Rafael R. Assis, Ana C. Torrecilhas, Elvira M. Saraiva, Natália L. Pessoa, Marco A. Campos, Eric F. Marialva, Cláudia M. Ríos-Velasquez, Felipe A. Pessoa, Nágila F. Secundino, Jerônimo N. Rugani, Elsa Nieves, Salvatore J. Turco, Maria N. Melo, Rodrigo P. Soares

Molecular and Cellular Biochemistry Faculty Publications

The immunomodulatory properties of lipophosphoglycans (LPG) from New World species of Leishmania have been assessed in Leishmania infantum and Leishmania braziliensis, the causative agents of visceral and cutaneous leishmaniasis, respectively. This glycoconjugate is highly polymorphic among species with variation in sugars that branch off the conserved Gal(β1,4)Man(α1)-PO4 backbone of repeat units. Here, the immunomodulatory activity of LPGs from Leishmania amazonensis, the causative agent of diffuse cutaneous leishmaniasis, was evaluated in two strains from Brazil. One strain (PH8) was originally isolated from the sand fly and the other (Josefa) was isolated from a human case. The ability of …

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Red-Shifted Aequorin Variants Incorporating Non-Canonical Amino Acids: Applications In In Vivo Imaging, Kristen M. Grinstead, Laura Rowe, Mark Ensor, Smita Joel, Pirouz Daftarian, Emre Dikici, Jean-Marc Zingg, Sylvia Daunert Jul 2016

Red-Shifted Aequorin Variants Incorporating Non-Canonical Amino Acids: Applications In In Vivo Imaging, Kristen M. Grinstead, Laura Rowe, Mark Ensor, Smita Joel, Pirouz Daftarian, Emre Dikici, Jean-Marc Zingg, Sylvia Daunert

Pharmaceutical Sciences Faculty Publications

The increased importance of in vivo diagnostics has posed new demands for imaging technologies. In that regard, there is a need for imaging molecules capable of expanding the applications of current state-of-the-art imaging in vivo diagnostics. To that end, there is a desire for new reporter molecules capable of providing strong signals, are non-toxic, and can be tailored to diagnose or monitor the progression of a number of diseases. Aequorin is a non-toxic photoprotein that can be used as a sensitive marker for bioluminescence in vivo imaging. The sensitivity of aequorin is due to the fact that bioluminescence is a …

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Ubr3, A Novel Modulator Of Hh Signaling Affects The Degradation Of Costal-2 And Kif7 Through Poly-Ubiquitination, Tongchao Li, Junkai Fan, Bernardo Blanco-Sánchez, Nikolaos Giagtzoglou, Guang Lin, Shinya Yamamoto, Manish Jaiswal, Kuchuan Chen, Jie Zhang, Wei Wei, Michael T. Lewis, Andrew K. Groves, Monte Westerfield, Jianhang Jia, Hugo J. Bellen May 2016

Ubr3, A Novel Modulator Of Hh Signaling Affects The Degradation Of Costal-2 And Kif7 Through Poly-Ubiquitination, Tongchao Li, Junkai Fan, Bernardo Blanco-Sánchez, Nikolaos Giagtzoglou, Guang Lin, Shinya Yamamoto, Manish Jaiswal, Kuchuan Chen, Jie Zhang, Wei Wei, Michael T. Lewis, Andrew K. Groves, Monte Westerfield, Jianhang Jia, Hugo J. Bellen

Markey Cancer Center Faculty Publications

Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require …

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Stabilin-Mediated Cellular Internalization Of Phosphorothioate-Modified Antisense Oligonucleotides (Asos), Colton M. Miller, Aaron J. Donner, Emma K. Blank, Andrew W. Egger, Brianna M. Kellar, Punit P. Seth, Edward N. Harris Apr 2016

Stabilin-Mediated Cellular Internalization Of Phosphorothioate-Modified Antisense Oligonucleotides (Asos), Colton M. Miller, Aaron J. Donner, Emma K. Blank, Andrew W. Egger, Brianna M. Kellar, Punit P. Seth, Edward N. Harris

UCARE: Research Products

Introduction: Antisense oligonucleotides (ASOs) are short chemically modified oligonucleotides (5-7.4 kDa) that can produce a pharmacological effect by binding to RNA and affecting intermediary metabolism. Over 35 phosphorothioate (PS) ASOs are at various stages of clinical development for use as therapeutic agents and pharmacological tools. Antisense therapy is a progressing area of research, as these small strands of nucleotide oligomers can be produced to silence genes that aggravate chronic disorders or infections. An important distinction for ASOs compared to DNA is the substitution of the phosphodiester (PO) backbone with the PS modification. This sulfur substitution allows for these polar polyanionic …

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Arf6 Controls Platelet Spreading And Clot Retraction Via Integrin ΑIibΒ3 Trafficking, Yunjie Huang, Smita Joshi, Binggang Xiang, Yasunori Kanaho, Zhenyu Li, Beth A. Bouchard, Carole L. Moncman, Sidney W. Whiteheart Mar 2016

Arf6 Controls Platelet Spreading And Clot Retraction Via Integrin ΑIibΒ3 Trafficking, Yunjie Huang, Smita Joshi, Binggang Xiang, Yasunori Kanaho, Zhenyu Li, Beth A. Bouchard, Carole L. Moncman, Sidney W. Whiteheart

Molecular and Cellular Biochemistry Faculty Publications

Platelet and megakaryocyte endocytosis is important for loading certain granule cargo (ie, fibrinogen [Fg] and vascular endothelial growth factor); however, the mechanisms of platelet endocytosis and its functional acute effects are understudied. Adenosine 5'-diphosphate–ribosylation factor 6 (Arf6) is a small guanosine triphosphate–binding protein that regulates endocytic trafficking, especially of integrins. To study platelet endocytosis, we generated platelet-specific Arf6 knockout (KO) mice. Arf6 KO platelets had less associated Fg suggesting that Arf6 affects αIIbβ3-mediated Fg uptake and/or storage. Other cargo was unaffected. To measure Fg uptake, mice were injected with biotinylated- or fluorescein isothiocyanate (FITC)–labeled Fg. Platelets …

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Effect Of Hydroxychloroquine And Characterization Of Autophagy In A Mouse Model Of Endometriosis, A. Ruiz, S. Rockfield, N. Taran, E. Haller, Robert Engelman, I Flores, P Panina-Bordignon, Meera Nanjundan Jan 2016

Effect Of Hydroxychloroquine And Characterization Of Autophagy In A Mouse Model Of Endometriosis, A. Ruiz, S. Rockfield, N. Taran, E. Haller, Robert Engelman, I Flores, P Panina-Bordignon, Meera Nanjundan

Molecular Biosciences Faculty Publications

In endometriosis, the increased survival potential of shed endometrial cells (which normally undergo anoikis) is suggested to promote lesion development. One mechanism that may alter anoikis is autophagy. Using an autophagic flux inhibitor hydroxychloroquine (HCQ), we identified that it reduces the in vitro survival capacity of human endometriotic and endometrial T-HESC cells. We also identified that HCQ could decrease lesion numbers and disrupt lesion histopathology, as well as increase the levels of peritoneal macrophages and the IP-10 (10 kDa interferon-γ-induced protein) chemokine in a mouse model of endometriosis. We noted that RNA levels of a subset of autophagic …

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Antibodies Against A Secreted Product Of Staphylococcus Aureus Trigger Phagocytic Killing, Lena Thomer, Carla Emolo, Vilasack Thammavongsa, Hwan Keun Kim, Molly E. Mcadow, Wenqi Yu, Matthew Kieffer, Olaf Schneewind, Dominique Missiakas Jan 2016

Antibodies Against A Secreted Product Of Staphylococcus Aureus Trigger Phagocytic Killing, Lena Thomer, Carla Emolo, Vilasack Thammavongsa, Hwan Keun Kim, Molly E. Mcadow, Wenqi Yu, Matthew Kieffer, Olaf Schneewind, Dominique Missiakas

Molecular Biosciences Faculty Publications

Host immunity against bacteria typically involves antibodies that recognize the microbial surface and promote phagocytic killing. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of lethal bloodstream infection; however, vaccines and antibody therapeutics targeting staphylococcal surface molecules have thus far failed to achieve clinical efficacy. S. aureus secretes coagulase (Coa), which activates host prothrombin and generates fibrin fibrils that protect the pathogen against phagocytosis by immune cells. Because of negative selection, the coding sequence for the prothrombin-binding D1-D2 domain is highly variable and does not elicit cross-protective immune responses. The R domain, tandem repeats of a 27-residue peptide that bind …

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It Is All About (U)Biquitin: Role Of Altered Ubiquitin-Proteasome System And Uchl1 In Alzheimer Disease, Antonella Tramutola, Fabio Di Domenico, Eugenio Barone, Marzia Perluigi, D. Allan Butterfield Jan 2016

It Is All About (U)Biquitin: Role Of Altered Ubiquitin-Proteasome System And Uchl1 In Alzheimer Disease, Antonella Tramutola, Fabio Di Domenico, Eugenio Barone, Marzia Perluigi, D. Allan Butterfield

Chemistry Faculty Publications

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency …

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Local Corticotropin Releasing Hormone (Crh) Signals To Its Receptor Crhr1 During Postnatal Development Of The Mouse Olfactory Bulb, Isabella Garcia, Paramjit K Bhullar, Burak Tepe, Joshua Ortiz-Guzman, Longwen Huang, Alexander M Herman, Lesley Chaboub, Benjamin Deneen, Nicholas J Justice, Benjamin R Arenkiel Jan 2016

Local Corticotropin Releasing Hormone (Crh) Signals To Its Receptor Crhr1 During Postnatal Development Of The Mouse Olfactory Bulb, Isabella Garcia, Paramjit K Bhullar, Burak Tepe, Joshua Ortiz-Guzman, Longwen Huang, Alexander M Herman, Lesley Chaboub, Benjamin Deneen, Nicholas J Justice, Benjamin R Arenkiel

Faculty, Staff and Students Publications

Neuropeptides play important physiological functions during distinct behaviors such as arousal, learning, memory, and reproduction. However, the role of local, extrahypothalamic neuropeptide signaling in shaping synapse formation and neuronal plasticity in the brain is not well understood. Here, we characterize the spatiotemporal expression profile of the neuropeptide corticotropin-releasing hormone (CRH) and its receptor CRHR1 in the mouse OB throughout development. We found that CRH-expressing interneurons are present in the external plexiform layer, that its cognate receptor is expressed by granule cells, and show that both CRH and CRHR1 expression enriches in the postnatal period when olfaction becomes important towards olfactory-related …

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A Cytosolic Multiprotein Complex Containing P85Α Is Required For Β-Catenin Activation In Colitis And Colitis-Associated Cancer, Tatiana Goretsky, Emily M. Bradford, Hyunji Ryu, Maryam Tahir, Mary Pat Moyer, Tianyan Gao, Linheng Li, Terrence A. Barrett Nov 2015

A Cytosolic Multiprotein Complex Containing P85Α Is Required For Β-Catenin Activation In Colitis And Colitis-Associated Cancer, Tatiana Goretsky, Emily M. Bradford, Hyunji Ryu, Maryam Tahir, Mary Pat Moyer, Tianyan Gao, Linheng Li, Terrence A. Barrett

Internal Medicine Faculty Publications

Wnt/β-catenin signaling is required for crypt structure maintenance. We previously observed nuclear accumulation of Ser-552 phosphorylated β-catenin (pβ-CatSer-552) in intestinal epithelial cells (IEC) during colitis and colitis-associated cancer. Data here delineate a novel multiprotein cytosolic complex (MCC) involved in β-catenin signaling in the intestine. The MCC contains p85α, the class IA subunit of PI3K, along with β-catenin, 14-3-3ζ, Akt, and p110α. MCC levels in IEC increase in colitis and colitis-associated cancer patients. IEC-specific p85α-deficient (p85ΔIEC) mice develop more severe dextran sodium …

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Autophagy Is Induced Upon Platelet Activation And Is Essential For Hemostasis And Thrombosis, Madhu M. Ouseph, Yunjie Huang, Meenakshi Banerjee, Smita Joshi, Laura Macdonald, Yu Zhong, Huijuan Liu, Xianting Li, Binggang Xiang, Guoying Zhang, Masaaki Komatsu, Zhenyu Yue, Zhenyu Li, Brian Storrie, Sidney W. Whiteheart, Qing Jun Wang Sep 2015

Autophagy Is Induced Upon Platelet Activation And Is Essential For Hemostasis And Thrombosis, Madhu M. Ouseph, Yunjie Huang, Meenakshi Banerjee, Smita Joshi, Laura Macdonald, Yu Zhong, Huijuan Liu, Xianting Li, Binggang Xiang, Guoying Zhang, Masaaki Komatsu, Zhenyu Yue, Zhenyu Li, Brian Storrie, Sidney W. Whiteheart, Qing Jun Wang

Molecular and Cellular Biochemistry Faculty Publications

Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knockout mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling …

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Proteasome-Mediated Proteolysis Of The Polyglutamine-Expanded Androgen Receptor Is A Late Event In Spinal And Bulbar Muscular Atrophy (Sbma) Pathogenesis., Erin M Heine, Tamar R Berger, Anna Pluciennik, Christopher R Orr, Lori Zboray, Diane E Merry May 2015

Proteasome-Mediated Proteolysis Of The Polyglutamine-Expanded Androgen Receptor Is A Late Event In Spinal And Bulbar Muscular Atrophy (Sbma) Pathogenesis., Erin M Heine, Tamar R Berger, Anna Pluciennik, Christopher R Orr, Lori Zboray, Diane E Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Proteolysis of polyglutamine-expanded proteins is thought to be a required step in the pathogenesis of several neurodegenerative diseases. The accepted view for many polyglutamine proteins is that proteolysis of the mutant protein produces a "toxic fragment" that induces neuronal dysfunction and death in a soluble form; toxicity of the fragment is buffered by its incorporation into amyloid-like inclusions. In contrast to this view, we show that, in the polyglutamine disease spinal and bulbar muscular atrophy, proteolysis of the mutant androgen receptor (AR) is a late event. Immunocytochemical and biochemical analyses revealed that the mutant AR aggregates as a full-length protein, …

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Transcriptional Activity Of The Islet Β Cell Factor Pdx1 Is Augmented By Lysine Methylation Catalyzed By The Methyltransferase Set7/9, Aarthi V. Maganti, Bernhard Maier, Sarah A. Tersey, Megan L. Sampley, Amber L. Mosley, Sabire Özcan, Boobalan Pachaiyappan, Patrick M. Woster, Chad S. Hunter, Roland Stein, Raghavendra G. Mirmira Apr 2015

Transcriptional Activity Of The Islet Β Cell Factor Pdx1 Is Augmented By Lysine Methylation Catalyzed By The Methyltransferase Set7/9, Aarthi V. Maganti, Bernhard Maier, Sarah A. Tersey, Megan L. Sampley, Amber L. Mosley, Sabire Özcan, Boobalan Pachaiyappan, Patrick M. Woster, Chad S. Hunter, Roland Stein, Raghavendra G. Mirmira

Molecular and Cellular Biochemistry Faculty Publications

The transcription factor Pdx1 is crucial to islet β cell function and regulates target genes in part through interaction with coregulatory factors. Set7/9 is a Lys methyltransferase that interacts with Pdx1. Here we tested the hypothesis that Lys methylation of Pdx1 by Set7/9 augments Pdx1 transcriptional activity. Using mass spectrometry and mutational analysis of purified proteins, we found that Set7/9 methylates the N-terminal residues Lys-123 and Lys-131 of Pdx1. Methylation of these residues occurred only in the context of intact, full-length Pdx1, suggesting a specific requirement of secondary and/or tertiary structural elements for catalysis by Set7/9. Immunoprecipitation assays and mass …

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Trail-Based High Throughput Screening Reveals A Link Between Trail-Mediated Apoptosis And Glutathione Reductase, A Key Component Of Oxidative Stress Response., Dmitri Rozanov, Anton Cheltsov, Eduard Sergienko, Stefan Vasile, Vladislav Golubkov, Alexander E Aleshin, Trevor Levin, Elie Traer, Byron Hann, Julia Freimuth, Nikita Alexeev, Max A Alekseyev, Sergey P Budko, Hans Peter Bächinger, Paul Spellman Jan 2015

Trail-Based High Throughput Screening Reveals A Link Between Trail-Mediated Apoptosis And Glutathione Reductase, A Key Component Of Oxidative Stress Response., Dmitri Rozanov, Anton Cheltsov, Eduard Sergienko, Stefan Vasile, Vladislav Golubkov, Alexander E Aleshin, Trevor Levin, Elie Traer, Byron Hann, Julia Freimuth, Nikita Alexeev, Max A Alekseyev, Sergey P Budko, Hans Peter Bächinger, Paul Spellman

Computational Biology Institute

A high throughput screen for compounds that induce TRAIL-mediated apoptosis identified ML100 as an active chemical probe, which potentiated TRAIL activity in prostate carcinoma PPC-1 and melanoma MDA-MB-435 cells. Follow-up in silico modeling and profiling in cell-based assays allowed us to identify NSC130362, pharmacophore analog of ML100 that induced 65-95% cytotoxicity in cancer cells and did not affect the viability of human primary hepatocytes. In agreement with the activation of the apoptotic pathway, both ML100 and NSC130362 synergistically with TRAIL induced caspase-3/7 activity in MDA-MB-435 cells. Subsequent affinity chromatography and inhibition studies convincingly demonstrated that glutathione reductase (GSR), a key …

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Myoepithelial Cell Morphogenesis And Differentiation In The Mouse Submandibular Salivary Gland In Development And Disease, Elise Marie Gervais Jan 2015

Myoepithelial Cell Morphogenesis And Differentiation In The Mouse Submandibular Salivary Gland In Development And Disease, Elise Marie Gervais

Legacy Theses & Dissertations (2009 - 2024)

Organogenesis is the process by which tissues organize, gain considerable size, and undergo cellular differentiation or specialization to form fully functional organs. To study the processes involved in organogenesis of branched organs, the mouse submandibular salivary gland is frequently used as a model system, as it can undergo morphogenesis and differentiation and be genetically manipulated ex vivo. The mouse submandibular salivary gland undergoes a specific process of outgrowth and invagination known as branching morphogenesis which allows for the significant increase in gland size and complexity, as well as maximization of surface area for secretion of saliva. Surrounding the mouse submandibular …

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Mtorc2 Is Required For Rit-Mediated Oxidative Stress Resistance, Weikang Cai, Douglas A. Andres Dec 2014

Mtorc2 Is Required For Rit-Mediated Oxidative Stress Resistance, Weikang Cai, Douglas A. Andres

Molecular and Cellular Biochemistry Faculty Publications

Rit, a member of the Ras family of GTPases, has been shown to promote cell survival in response to oxidative stress, in part by directing an evolutionarily conserved p38 MAPK-Akt survival cascade. Aberrant Rit signaling has recently been implicated as a driver mutation in human cancer, adding importance to the characterization of critical Rit effector pathways. However, the mechanism by which Rit-p38 signaling regulated Akt activity was unknown. Here, we identify mTORC2 as a critical downstream mediator of Rit-dependent survival signaling in response to reactive oxygen species (ROS) stress. Rit interacts with Sin1 (MAPKAP1), and Rit loss compromises ROS-dependent mTORC2 …

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Transcription Of The Streptococcus Pyogenes Hyaluronic Acid Capsule Biosynthesis Operon Is Regulated By Previously Unknown Upstream Elements, Marina Falaleeva, Oliwia W. Zurek, Robert L. Watkins, Robert W. Reed, Hadeel Ali, Paul Sumby, Jovanka M. Voyich, Natalia Korotkova Dec 2014

Transcription Of The Streptococcus Pyogenes Hyaluronic Acid Capsule Biosynthesis Operon Is Regulated By Previously Unknown Upstream Elements, Marina Falaleeva, Oliwia W. Zurek, Robert L. Watkins, Robert W. Reed, Hadeel Ali, Paul Sumby, Jovanka M. Voyich, Natalia Korotkova

Molecular and Cellular Biochemistry Faculty Publications

The important human pathogen Streptococcus pyogenes (group A Streptococcus [GAS]) produces a hyaluronic acid (HA) capsule that plays critical roles in immune evasion. Previous studies showed that the hasABC operon encoding the capsule biosynthesis enzymes is under the control of a single promoter, P1, which is negatively regulated by the two-component regulatory system CovR/S. In this work, we characterize the sequence upstream of P1 and identify a novel regulatory region controlling transcription of the capsule biosynthesis operon in the M1 serotype strain MGAS2221. This region consists of a promoter, P2, which initiates transcription of a novel small RNA, HasS, an …

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Measuring The Role Of Inhibition In Auditory Discrimination In Mice, Tazima Nur Dec 2014

Measuring The Role Of Inhibition In Auditory Discrimination In Mice, Tazima Nur

Graduate Theses and Dissertations

Understanding how inhibitory neurons affect sensory information processing in the cerebral cortex is an ongoing goal of both neuroscience and statistical physics research. In this master's thesis research project, an experimental system has been designed and built for studying how auditory dynamic range depends on inhibitory neurons, based on observations of mouse behavior. In this thesis, firstly, the topic of inhibition and information processing has been introduced. Then two papers related to inhibition and dynamic range has been reviewed in detail. One of the papers is an experimental work that analyzes the affect of inhibition on dynamic range. The other …

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Deficiency Of Kruppel-Like Factor Klf4 In Myeloid-Derived Suppressor Cells Inhibits Tumor Pulmonary Metastasis In Mice Accompanied By Decreased Fibrocytes, Y. Shi, L. Ou, S. Han, M. Li, M. M. O. Pena, E. A. Pena, Chunming Liu, M. Nagarkatti, D. Fan, W. Ai Nov 2014

Deficiency Of Kruppel-Like Factor Klf4 In Myeloid-Derived Suppressor Cells Inhibits Tumor Pulmonary Metastasis In Mice Accompanied By Decreased Fibrocytes, Y. Shi, L. Ou, S. Han, M. Li, M. M. O. Pena, E. A. Pena, Chunming Liu, M. Nagarkatti, D. Fan, W. Ai

Molecular and Cellular Biochemistry Faculty Publications

The importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) bearing monocyte markers in tumor metastasis has been well established. Recently, it was reported that these cells possess phenotypic plasticity and differentiate into fibrocytes, very distinct cells that are precursors of tumorigenic myofibroblasts. However, the importance of this transdifferentiation in tumor metastasis has not been explored. Here, we describe the role of MDSC-derived fibrocytes in tumor metastasis that is regulated by Kruppel-like factor 4 (KLF4), a transcription factor that is critical to monocyte differentiation and to promotion of cancer development. Using mouse metastasis models of melanoma and breast cancer, we found that …

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The Formin Fmnl3 Assembles Plasma Membrane Protrusions That Participate In Cell–Cell Adhesion, Timothy J. Gauvin, Lorna E. Young, Henry N. Higgs Nov 2014

The Formin Fmnl3 Assembles Plasma Membrane Protrusions That Participate In Cell–Cell Adhesion, Timothy J. Gauvin, Lorna E. Young, Henry N. Higgs

Dartmouth Scholarship

FMNL3 is a vertebrate-specific formin protein previously shown to play a role in angiogenesis and cell migration. Here we define the cellular localization of endogenous FMNL3, the dynamics of GFP-tagged FMNL3 during cell migration, and the effects of FMNL3 suppression in mammalian culture cells. The majority of FMNL3 localizes in a punctate pattern, with >95% of these puncta being indistinguishable from the plasma membrane by fluorescence microscopy. A small number of dynamic cytoplasmic FMNL3 patches also exist, which enrich near cell–cell contact sites and fuse with the plasma membrane at these sites. These cytoplasmic puncta appear to be part of …

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Kynurenine Aminotransferase Iii And Glutamine Transaminase L Are Identical Enzymes That Have Cysteine S-Conjugate Beta-Lyase Activity And Can Transaminate L-Selenomethionine, John T. Pinto, Boris F. Krasnikov, Steven Alcutt, Melanie E. Jones, Thambi Dorai, Arthur J L Cooper Nov 2014

Kynurenine Aminotransferase Iii And Glutamine Transaminase L Are Identical Enzymes That Have Cysteine S-Conjugate Beta-Lyase Activity And Can Transaminate L-Selenomethionine, John T. Pinto, Boris F. Krasnikov, Steven Alcutt, Melanie E. Jones, Thambi Dorai, Arthur J L Cooper

NYMC Faculty Publications

Three of the four kynurenine aminotransferases (KAT I, II, and IV) that synthesize kynurenic acid, a neuromodulator, are identical to glutamine transaminase K (GTK), α-aminoadipate aminotransferase, and mitochondrial aspartate aminotransferase, respectively. GTK/KAT I and aspartate aminotransferase/KAT IV possess cysteine S-conjugate β-lyase activity. The gene for the former enzyme, GTK/KAT I, is listed in mammalian genome data banks as CCBL1 (cysteine conjugate beta-lyase 1). Also listed, despite the fact that no β-lyase activity has been assigned to the encoded protein in the genome data bank, is a CCBL2 (synonym KAT III). We show that human KAT III/CCBL2 possesses cysteine S-conjugate β-lyase …

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Coprinus Comatus Cap Inhibits Adipocyte Differentiation Via Regulation Of Pparγ And Akt Signaling Pathway, Hyoung Joon Park, Jisoo Yun, Hong-Duck Kim, Chung-Kil Won, Gon-Sup Kim, Jae-Hyeon Cho Sep 2014

Coprinus Comatus Cap Inhibits Adipocyte Differentiation Via Regulation Of Pparγ And Akt Signaling Pathway, Hyoung Joon Park, Jisoo Yun, Hong-Duck Kim, Chung-Kil Won, Gon-Sup Kim, Jae-Hyeon Cho

NYMC Faculty Publications

This study assessed the effects of Coprinus comatus cap (CCC) on adipogenesis in 3T3-L1 adipocytes and the effects of CCC on the development of diet-induced obesity in rats. Here, we showed that the CCC has an inhibitory effect on the adipocyte differentiation of 3T3-L1 cells, resulting in a significant decrease in lipid accumulation through the downregulation of several adipocyte specific-transcription factors, including CCAAT/enhancer binding protein β, C/EBPδ, and peroxisome proliferator-activated receptor gamma (PPARγ). Moreover, treatment with CCC during adipocyte differentiation induced a significant down-regulation of PPARγ and adipogenic target genes, including adipocyte protein 2, lipoprotein lipase, and adiponectin. Interestingly, the …

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