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Cellular and Molecular Physiology

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Articles 1 - 30 of 330

Full-Text Articles in Cell Biology

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 ...


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 ...


Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz Sep 2019

Expression Of Mitochondrial Membrane-Linked Sab Determines Severity Of Sex-Dependent Acute Liver Injury, Sanda Win, Robert W. M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W. M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, Neil Kaplowitz

University of Massachusetts Medical School Faculty Publications

SAB is an outer membrane docking protein for JNK mediated impaired mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. Current work demonstrated that increasing SAB enhanced the severity of APAP liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression versus males. The mechanism of SAB repression involved a pathway from ERalpha to p53 expression which induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB in females leading to increased injury from APAP and TNF ...


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 ...


The Central Role Of The Tail In Switching Off 10s Myosin Ii Activity, Shixin Yang, Kyounghwan Lee, John L. Woodhead, Osamu Sato, Mitsuo Ikebe, Roger Craig Sep 2019

The Central Role Of The Tail In Switching Off 10s Myosin Ii Activity, Shixin Yang, Kyounghwan Lee, John L. Woodhead, Osamu Sato, Mitsuo Ikebe, Roger Craig

Radiology Publications and Presentations

Myosin II is a motor protein with two heads and an extended tail that plays an essential role in cell motility. Its active form is a polymer (myosin filament) that pulls on actin to generate motion. Its inactive form is a monomer with a compact structure (10S sedimentation coefficient), in which the tail is folded and the two heads interact with each other, inhibiting activity. This conformation is thought to function in cells as an energy-conserving form of the molecule suitable for storage as well as transport to sites of filament assembly. The mechanism of inhibition of the compact molecule ...


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 ...


Modeling Of Cisplatin-Induced Signaling Dynamics In Triple-Negative Breast Cancer Cells Reveals Mediators Of Sensitivity, Anne Margriet Heijink, Marieke Everts, Megan E. Honeywell, Ryan Richards, Yannick P. Kok, Elisabeth G. E. De Vries, Michael J. Lee, Marcel A T M Van Vugt Aug 2019

Modeling Of Cisplatin-Induced Signaling Dynamics In Triple-Negative Breast Cancer Cells Reveals Mediators Of Sensitivity, Anne Margriet Heijink, Marieke Everts, Megan E. Honeywell, Ryan Richards, Yannick P. Kok, Elisabeth G. E. De Vries, Michael J. Lee, Marcel A T M Van Vugt

Open Access Articles

Triple-negative breast cancers (TNBCs) display great diversity in cisplatin sensitivity that cannot be explained solely by cancer-associated DNA repair defects. Differential activation of the DNA damage response (DDR) to cisplatin has been proposed to underlie the observed differential sensitivity, but it has not been investigated systematically. Systems-level analysis-using quantitative time-resolved signaling data and phenotypic responses, in combination with mathematical modeling-identifies that the activation status of cell-cycle checkpoints determines cisplatin sensitivity in TNBC cell lines. Specifically, inactivation of the cell-cycle checkpoint regulator MK2 or G3BP2 sensitizes cisplatin-resistant TNBC cell lines to cisplatin. Dynamic signaling data of five cell cycle-related signals predicts ...


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 ...


Mtf1, A Classic Metal Sensing Transcription Factor, Promotes Myogenesis In Response To Copper, Cristina Tavera-Montañez, Sarah J. Hainer, Daniella Cangussu, Shellaina J. V. Gordon, Yao Xiao, Pablo Reyes-Gutierrez, Anthony N. Imbalzano, Juan G. Navea, Thomas G. Fazzio, Teresita Padilla-Benavides Jun 2019

Mtf1, A Classic Metal Sensing Transcription Factor, Promotes Myogenesis In Response To Copper, Cristina Tavera-Montañez, Sarah J. Hainer, Daniella Cangussu, Shellaina J. V. Gordon, Yao Xiao, Pablo Reyes-Gutierrez, Anthony N. Imbalzano, Juan G. Navea, Thomas G. Fazzio, Teresita Padilla-Benavides

University of Massachusetts Medical School Faculty Publications

MTF1 is a conserved metal-binding transcription factor in eukaryotes that binds to conserved DNA sequence motifs, termed metal response elements (MREs). MTF1 responds to metal excess and deprivation, protects cells from oxidative and hypoxic stresses, and is required for embryonic development in vertebrates. We used multiple strategies to identify an unappreciated role for MTF1 and copper (Cu) in cell differentiation. Upon initiation of myogenesis from primary myoblasts, MTF1 expression increased, as did nuclear localization. Mtf1 knockdown impaired differentiation, while addition of non-toxic concentrations of Cu+ enhanced MTF1 expression and promoted myogenesis. Cu+ bound stoichiometrically to a C-terminus tetra-cysteine of MTF1 ...


Proteome Of The Central Apparatus Of A Ciliary Axoneme, Lei Zhao, Yuqing Hou, Tyler Picariello, Branch Craige, George B. Witman Jun 2019

Proteome Of The Central Apparatus Of A Ciliary Axoneme, Lei Zhao, Yuqing Hou, Tyler Picariello, Branch Craige, George B. Witman

Radiology Publications and Presentations

Nearly all motile cilia have a "9+2" axoneme containing a central apparatus (CA), consisting of two central microtubules with projections, that is essential for motility. To date, only 22 proteins are known to be CA components. To identify new candidate CA proteins, we used mass spectrometry to compare axonemes of wild-type Chlamydomonas and a CA-less mutant. We identified 44 novel candidate CA proteins, of which 13 are conserved in humans. Five of the latter were studied more closely, and all five localized to the CA; therefore, most of the other candidates are likely to also be CA components. Our ...


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 ...


Jnk(1/2) Represses Lkb(1)-Deficiency-Induced Lung Squamous Cell Carcinoma Progression, Jian Liu, Tianyuan Wang, Chad J. Creighton, San-Pin Wu, Madhumita Ray, Kyathanahalli S. Janardhan, Cynthia J. Willson, Sung-Nam Cho, Patricia D. Castro, Michael M. Ittmann, Jian-Liang Li, Roger J. Davis, Francesco J. Demayo May 2019

Jnk(1/2) Represses Lkb(1)-Deficiency-Induced Lung Squamous Cell Carcinoma Progression, Jian Liu, Tianyuan Wang, Chad J. Creighton, San-Pin Wu, Madhumita Ray, Kyathanahalli S. Janardhan, Cynthia J. Willson, Sung-Nam Cho, Patricia D. Castro, Michael M. Ittmann, Jian-Liang Li, Roger J. Davis, Francesco J. Demayo

Open Access Articles

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing DeltaNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKalpha and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1 ...


Ouabain Enhances Cell-Cell Adhesion Mediated By Beta1 Subunits Of The Na(+),K(+)-Atpase In Cho Fibroblasts, Claudia Andrea Vilchis-Nestor, Maria Luisa Roldan, Angelina Leonardi, Juan G. Navea, Teresita Padilla-Benavides, Liora Shoshani Apr 2019

Ouabain Enhances Cell-Cell Adhesion Mediated By Beta1 Subunits Of The Na(+),K(+)-Atpase In Cho Fibroblasts, Claudia Andrea Vilchis-Nestor, Maria Luisa Roldan, Angelina Leonardi, Juan G. Navea, Teresita Padilla-Benavides, Liora Shoshani

Open Access Articles

Adhesion is a crucial characteristic of epithelial cells to form barriers to pathogens and toxic substances from the environment. Epithelial cells attach to each other using intercellular junctions on the lateral membrane, including tight and adherent junctions, as well as the Na(+),K(+)-ATPase. Our group has shown that non-adherent chinese hamster ovary (CHO) cells transfected with the canine beta1 subunit become adhesive, and those homotypic interactions amongst beta1 subunits of the Na(+),K(+)-ATPase occur between neighboring epithelial cells. Ouabain, a cardiotonic steroid, binds to the alpha subunit of the Na(+),K(+)-ATPase, inhibits the pump activity and induces ...


Inhibition Of Triggering Receptor Expressed On Myeloid Cells 1 Ameliorates Inflammation And Macrophage And Neutrophil Activation In Alcoholic Liver Disease In Mice, David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo Mar 2019

Inhibition Of Triggering Receptor Expressed On Myeloid Cells 1 Ameliorates Inflammation And Macrophage And Neutrophil Activation In Alcoholic Liver Disease In Mice, David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo

Gyongyi Szabo

Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage- and pathogen-associated molecular patterns contribute to a self-perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a surface receptor that amplifies inflammation induced by toll-like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM-1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand-independent TREM-1 inhibitory peptides that were formulated into human high-density lipoprotein (HDL)-mimicking complexes GF9-HDL and GA ...


Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak Mar 2019

Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak

Katherine A. Fitzgerald

Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS ...


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 ...


Brg1 Is A Prognostic Indicator And A Potential Therapeutic Target For Prostate Cancer, Rohini Muthuswami, Leeann Bailey, Radhakrishnan Rakesh, Anthony N. Imbalzano, Jeffrey A. Nickerson, Joel W. Hockensmith Jan 2019

Brg1 Is A Prognostic Indicator And A Potential Therapeutic Target For Prostate Cancer, Rohini Muthuswami, Leeann Bailey, Radhakrishnan Rakesh, Anthony N. Imbalzano, Jeffrey A. Nickerson, Joel W. Hockensmith

University of Massachusetts Medical School Faculty Publications

Brahma-related gene 1 (BRG1) is one of two mutually exclusive ATPases that function as the catalytic subunit of human SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling enzymes. BRG1 has been identified as a tumor suppressor in some cancer types but has been shown to be expressed at elevated levels, relative to normal tissue, in other cancers. Using TCGA (The Cancer Genome Atlas) prostate cancer database, we determined that BRG1 mRNA and protein expression is elevated in prostate tumors relative to normal prostate tissue. Only 3 of 491 (0.6%) sequenced tumors showed amplification of the locus or mutation in the ...


The Effects Of A Ketone Body On Synaptic Transmission, Alexandra Elizabeth Stanback Jan 2019

The Effects Of A Ketone Body On Synaptic Transmission, Alexandra Elizabeth Stanback

Theses and Dissertations--Biology

The ketogenic diet is commonly used to control epilepsy, especially in cases when medications cannot. The diet typically consists of high fat, low carb, and adequate protein and produces a metabolite called acetoacetate. Seizure activity is characterized by glutamate excitotoxicity and therefore glutamate regulation is a point of research for control of these disorders. Acetoacetate is heavily implicated as the primary molecule responsible for decreasing glutamate in the synapse; it is believed that acetoacetate interferes with the transport of glutamate into the synaptic vesicles. The effects on synaptic transmission at glutamatergic synapses was studied in relation to the ketogenic diet ...


Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak Jan 2019

Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak

Open Access Articles

Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS ...


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 ...


The Nf-Kappab Factor Relish Regulates Atg1 Expression And Controls Autophagy, Anubhab Nandy, Lin Lin, Panagiotis D. Velentzas, Louisa P. Wu, Eric H. Baehrecke, Neal S. Silverman Nov 2018

The Nf-Kappab Factor Relish Regulates Atg1 Expression And Controls Autophagy, Anubhab Nandy, Lin Lin, Panagiotis D. Velentzas, Louisa P. Wu, Eric H. Baehrecke, Neal S. Silverman

Open Access Articles

Macroautophagy and cell death both contribute to innate immunity, but little is known about how these processes integrate. Drosophila larval salivary glands require autophagy for developmentally programmed cell death, and innate immune signaling factors increase in these dying cells. Here, we show that the nuclear factor kappaB (NF-kappaB) factor Relish, a component of the immune deficiency (Imd) pathway, is required for salivary gland degradation. Surprisingly, of the classic Imd pathway components, only Relish and the PGRP receptors were involved in salivary gland degradation. Significantly, Relish controls salivary gland degradation by regulating autophagy but not caspases. In addition, expression of either ...


Crispr-Delivery Particles Targeting Nuclear Receptor-Interacting Protein 1 (Nrip1) In Adipose Cells To Enhance Energy Expenditure, Yuefei Shen, Jessica L. Cohen, Sarah M. Nicoloro, Mark Kelly, Batuhan Yenilmez, Felipe Henriques, Emmanouela Tsagkaraki, Yvonne J. K. Edwards, Xiaodi Hu, Randall H. Friedline, Jason K. Kim, Michael P. Czech Nov 2018

Crispr-Delivery Particles Targeting Nuclear Receptor-Interacting Protein 1 (Nrip1) In Adipose Cells To Enhance Energy Expenditure, Yuefei Shen, Jessica L. Cohen, Sarah M. Nicoloro, Mark Kelly, Batuhan Yenilmez, Felipe Henriques, Emmanouela Tsagkaraki, Yvonne J. K. Edwards, Xiaodi Hu, Randall H. Friedline, Jason K. Kim, Michael P. Czech

Open Access Articles

RNA-guided, engineered nucleases derived from the prokaryotic adaptive immune system CRISPR-Cas represent a powerful platform for gene deletion and editing. When used as a therapeutic approach, direct delivery of Cas9 protein and single-guide RNA (sgRNA) could circumvent the safety issues associated with plasmid delivery and therefore represents an attractive tool for precision genome engineering. Gene deletion or editing in adipose tissue to enhance its energy expenditure, fatty acid oxidation, and secretion of bioactive factors through a "browning" process presents a potential therapeutic strategy to alleviate metabolic disease. Here, we developed "CRISPR-delivery particles," denoted CriPs, composed of nano-size complexes of Cas9 ...


Activation Of The Apoptotic Pathway During Prolonged Prometaphase Blocks Daughter Cell Proliferation, Yumi Uetake, Greenfield Sluder Nov 2018

Activation Of The Apoptotic Pathway During Prolonged Prometaphase Blocks Daughter Cell Proliferation, Yumi Uetake, Greenfield Sluder

Radiology Publications and Presentations

When untransformed human cells spend >1.5 hr. in prometaphase under standard culture conditions, all daughters arrest in G1 despite normal division of their mothers. We investigate what happens during prolonged prometaphase that leads to daughter cell arrest in the absence of DNA damage. We find that progressive loss of anti-apoptotic MCL-1 activity and oxidative stress act in concert to partially activate the apoptosis pathway resulting in the delayed death of some daughters and senescence for the rest. At physiological oxygen levels, longer prometaphase durations are needed for all daughters to arrest. Partial activation of apoptosis during prolonged prometaphase leads ...


Inhibition Of Triggering Receptor Expressed On Myeloid Cells 1 Ameliorates Inflammation And Macrophage And Neutrophil Activation In Alcoholic Liver Disease In Mice, David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo Oct 2018

Inhibition Of Triggering Receptor Expressed On Myeloid Cells 1 Ameliorates Inflammation And Macrophage And Neutrophil Activation In Alcoholic Liver Disease In Mice, David Tornai, Istvan Furi, Zu T. Shen, Alexander B. Sigalov, Sahin Coban, Gyongyi Szabo

Open Access Articles

Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage- and pathogen-associated molecular patterns contribute to a self-perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a surface receptor that amplifies inflammation induced by toll-like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM-1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand-independent TREM-1 inhibitory peptides that were formulated into human high-density lipoprotein (HDL)-mimicking complexes GF9-HDL and GA ...


Modified Cantilever Arrays Improve Sensitivity And Reproducibility Of Nanomechanical Sensing In Living Cells, Samadhan B. Patil, Rajai M. Al-Jehani, Hashem Etayash, Valerian Turbe, Keren Jiang, Joe Bailey, Walid Al-Akkad, Rania Soudy, Kamaljit Kaur, Rachel A. Mckendry, Thomas Thundat, Joseph W. Ndieyira Oct 2018

Modified Cantilever Arrays Improve Sensitivity And Reproducibility Of Nanomechanical Sensing In Living Cells, Samadhan B. Patil, Rajai M. Al-Jehani, Hashem Etayash, Valerian Turbe, Keren Jiang, Joe Bailey, Walid Al-Akkad, Rania Soudy, Kamaljit Kaur, Rachel A. Mckendry, Thomas Thundat, Joseph W. Ndieyira

Pharmacy Faculty Articles and Research

Mechanical signaling involved in molecular interactions lies at the heart of materials science and biological systems, but the mechanisms involved are poorly understood. Here we use nanomechanical sensors and intact human cells to provide unique insights into the signaling pathways of connectivity networks, which deliver the ability to probe cells to produce biologically relevant, quantifiable and reproducible signals. We quantify the mechanical signals from malignant cancer cells, with 10 cells per ml in 1000-fold excess of non-neoplastic human epithelial cells. Moreover, we demonstrate that a direct link between cells and molecules creates a continuous connectivity which acts like a percolating ...


Identification Of A Novel Anoikis Signalling Pathway Using The Fungal Virulence Factor Gliotoxin, Florian Haun, Simon Neumann, Lukas Peintner, Katrin Wieland, Juri Habicht, Carsten Schwan, Kristine Ostevold, Maria Magdalena Koczorowska, Martin Biniossek, Matthias Kist, Hauke Busch, Melanie Boerries, Roger J. Davis, Ulrich Maurer, Oliver Schilling, Klaus Aktories, Christoph Borner Aug 2018

Identification Of A Novel Anoikis Signalling Pathway Using The Fungal Virulence Factor Gliotoxin, Florian Haun, Simon Neumann, Lukas Peintner, Katrin Wieland, Juri Habicht, Carsten Schwan, Kristine Ostevold, Maria Magdalena Koczorowska, Martin Biniossek, Matthias Kist, Hauke Busch, Melanie Boerries, Roger J. Davis, Ulrich Maurer, Oliver Schilling, Klaus Aktories, Christoph Borner

Open Access Articles

Anoikis is a form of apoptosis induced by cell detachment. Integrin inactivation plays a major role in the process but the exact signalling pathway is ill-defined. Here we identify an anoikis pathway using gliotoxin (GT), a virulence factor of the fungus Aspergillus fumigatus, which causes invasive aspergillosis in humans. GT prevents integrin binding to RGD-containing extracellular matrix components by covalently modifying cysteines in the binding pocket. As a consequence, focal adhesion kinase (FAK) is inhibited resulting in dephosphorylation of p190RhoGAP, allowing activation of RhoA. Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim. Cells in ...


A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder Aug 2018

A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder

Open Access Articles

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell ...


Are Membranes Non-Apoptotic Compartments For Apoptotic Caspases, Andreas Bergmann Aug 2018

Are Membranes Non-Apoptotic Compartments For Apoptotic Caspases, Andreas Bergmann

Open Access Articles

Critical mediators of apoptotic cell death are caspases, a highly specialized class of Cys-proteases that cleave substrates after Asp residues. Under normal conditions, caspases are cytosolic proteins. After their activation, they cleave a large number of cytosolic proteins and execute apoptosis (Figure 1, left). However, in addition to their well-studied role in apoptosis, caspases also have many non-apoptotic functions [1, 2]. It is not very well understood how cells escape the potential harmful action of caspases when they perform nonapoptotic functions. In our recent work, we now show that epithelial cells may prevent apoptosis by sequestration of caspases at the ...