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Full-Text Articles in Life Sciences

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 ...


The Genome-Wide Multi-Layered Architecture Of Chromosome Pairing In Early Drosophila Embryos, Jelena Erceg, Jumana Alhaj Abed, Anton Goloborodko, Bryan R. Lajoie, Geoffrey Fudenberg, Nezar Abdennur, Maxim Imakaev, Ruth B. Mccole, Son C. Nguyen, Wren Saylor, Eric F. Joyce, T. Niroshini Senaratne, Mohammed A. Hannan, Guy Nir, Job Dekker, Leonid A. Mirny, C-Ting Wu Oct 2019

The Genome-Wide Multi-Layered Architecture Of Chromosome Pairing In Early Drosophila Embryos, Jelena Erceg, Jumana Alhaj Abed, Anton Goloborodko, Bryan R. Lajoie, Geoffrey Fudenberg, Nezar Abdennur, Maxim Imakaev, Ruth B. Mccole, Son C. Nguyen, Wren Saylor, Eric F. Joyce, T. Niroshini Senaratne, Mohammed A. Hannan, Guy Nir, Job Dekker, Leonid A. Mirny, C-Ting Wu

Program in Systems Biology Publications and Presentations

Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focus on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first address long-standing questions regarding the structure of embryonic homolog pairing and, to this end, develop a haplotype-resolved Hi-C approach to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This computational approach, which we call Ohm, reveals pairing to be surprisingly structured genome-wide, with trans-homolog domains, compartments, and interaction peaks, many coinciding with analogous cis features. We also find a ...


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 ...


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 ...


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 ...


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 ...


Distinct Features Of Nucleolus-Associated Domains In Mouse Embryonic Stem Cells, Aizhan Bizhanova, Aimin Yan, Jun Yu, Lihua Julie Zhu, Paul D. Kaufman Aug 2019

Distinct Features Of Nucleolus-Associated Domains In Mouse Embryonic Stem Cells, Aizhan Bizhanova, Aimin Yan, Jun Yu, Lihua Julie Zhu, Paul D. Kaufman

University of Massachusetts Medical School Faculty Publications

Background Heterochromatin in eukaryotic interphase cells frequently localizes to the nucleolar periphery (nucleolus-associated domains, NADs) and the nuclear lamina (lamina-associated domains, LADs). Gene expression in somatic cell NADs is generally low, but NADs have not been characterized in mammalian stem cells.

Results Here, we generated the first genome-wide map of NADs in mouse embryonic stem cells (mESCs) via deep sequencing of chromatin associated with biochemically-purified nucleoli. As we had observed in mouse embryonic fibroblasts (MEFs), the large Type I subset of NADs overlaps with constitutive LADs and is enriched for features of constitutive heterochromatin, including late replication timing and low ...


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 ...


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 Zuñiga-Eulogio, Arvey Tacuba-Saavedra, Magdalena Bueno-Salgado, Andrea Sánchez-Carvajal, Yovani Vargas-Santiago, Miguel A. Mendoza-Catalán, Eduardo Pérez Salazar, Alejandra García-Hernández, Teresita Padilla-Benavides, Napoleón Navarro-Tito Aug 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 Zuñiga-Eulogio, Arvey Tacuba-Saavedra, Magdalena Bueno-Salgado, Andrea Sánchez-Carvajal, Yovani Vargas-Santiago, Miguel A. Mendoza-Catalán, Eduardo Pérez Salazar, Alejandra García-Hernández, Teresita Padilla-Benavides, Napoleón Navarro-Tito

University of Massachusetts Medical School Faculty Publications

Leptin is one of the main adipokines secreted in breast tissue, and has been associated with epithelial-mesenchymal transition (EMT) and tumor progression in breast cancer. Leptin promotes EMT, cell migration and invasion in epithelial breast cells, leading to tumor progression. However, the molecular mechanism that underlies these events is not fully understood; however, the activation of different signaling pathways appears to be essential. In this sense, the effect of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, has not been completely described. Therefore, we investigated the involvement of these ...


Multimodal Quantitative Imaging Of Brain Cancer In Cultured Cells, Xin Feng, Alona Muzikansky, Alonzo H. Ross, Michael R. Hamblin, Peter R. Jermain, Anna N. Yaroslavsky Jul 2019

Multimodal Quantitative Imaging Of Brain Cancer In Cultured Cells, Xin Feng, Alona Muzikansky, Alonzo H. Ross, Michael R. Hamblin, Peter R. Jermain, Anna N. Yaroslavsky

Open Access Articles

Fluorescence emission, polarization and subcellular localization of methylene blue (MB) were studied in four cancerous and two normal human brain cell lines. Fluorescence emission and polarization images were acquired and analyzed. The co-localization of MB with mitochondria, lysosomes and nuclei of the cells was evaluated. Glioblastoma cells exhibited significantly higher MB fluorescence polarization compared to normal astrocytes. Preferential accumulation of MB in mitochondria of glioblastoma cells may explain higher fluorescence polarization values in cancer cells as compared to normal. These findings may lead to the development of a quantitative method for the detection of brain cancer in single cells.


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 ...


Tethering Of Vesicles To The Golgi By Gmap210 Controls Lat Delivery To The Immune Synapse, Andres Ernesto Zucchetti, Laurence Bataille, Jean-Marie Carpier, Stephanie Dogniaux, Mabel San Roman-Jouve, Mathieu Maurin, Michael W. Stuck, Rosa M. Rios, Cosima T. Baldari, Gregory J. Pazour, Claire Hivroz Jun 2019

Tethering Of Vesicles To The Golgi By Gmap210 Controls Lat Delivery To The Immune Synapse, Andres Ernesto Zucchetti, Laurence Bataille, Jean-Marie Carpier, Stephanie Dogniaux, Mabel San Roman-Jouve, Mathieu Maurin, Michael W. Stuck, Rosa M. Rios, Cosima T. Baldari, Gregory J. Pazour, Claire Hivroz

Open Access Articles

The T cell immune synapse is a site of intense vesicular trafficking. Here we show that the golgin GMAP210, known to capture vesicles and organize membrane traffic at the Golgi, is involved in the vesicular transport of LAT to the immune synapse. Upon activation, more GMAP210 interact with LAT-containing vesicles and go together with LAT to the immune synapse. Regulating LAT recruitment and LAT-dependent signaling, GMAP210 controls T cell activation. Using a rerouting and capture assay, we show that GMAP210 captures VAMP7-decorated vesicles. Overexpressing different domains of GMAP210, we also show that GMAP210 allows their specific delivery to the immune ...


Somatic Molecular Analysis Augments Cytologic Evaluation Of Pancreatic Cyst Fluids As A Diagnostic Tool, Ali Sakhdari, Parnian Ahmadi Moghaddam, Chi Young Ok, Otto Walter, Keith Tomaszewicz, Mandi-Lee Caporelli, Xiuling Meng, Jennifer Lafemina, Giles F. Whalen, Edward Belkin, Jaroslav Zivny, Wahid Y. Wassef, Bruce A. Woda, Lloyd Hutchinson, Ediz F. Cosar Jun 2019

Somatic Molecular Analysis Augments Cytologic Evaluation Of Pancreatic Cyst Fluids As A Diagnostic Tool, Ali Sakhdari, Parnian Ahmadi Moghaddam, Chi Young Ok, Otto Walter, Keith Tomaszewicz, Mandi-Lee Caporelli, Xiuling Meng, Jennifer Lafemina, Giles F. Whalen, Edward Belkin, Jaroslav Zivny, Wahid Y. Wassef, Bruce A. Woda, Lloyd Hutchinson, Ediz F. Cosar

Open Access Articles

Objective: Better tools are needed for early diagnosis and classification of pancreatic cystic lesions (PCL) to trigger intervention before neoplastic precursor lesions progress to adenocarcinoma. We evaluated the capacity of molecular analysis to improve the accuracy of cytologic diagnosis for PCL with an emphasis on non-diagnostic/negative specimens.

Design: In a span of 7 years, at a tertiary care hospital, 318 PCL endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) were evaluated by cytologic examination and molecular analysis. Mucinous PCL were identified based on a clinical algorithm and 46 surgical resections were used to verify this approach. The mutation allele frequency (MAF ...


Ste5 Membrane Localization Allows Mapk Pathway Signaling In Trans Between Kinases On Separate Scaffold Molecules, Rachel E. Lamson, Matthew J. Winters, Peter M. Pryciak Jun 2019

Ste5 Membrane Localization Allows Mapk Pathway Signaling In Trans Between Kinases On Separate Scaffold Molecules, Rachel E. Lamson, Matthew J. Winters, Peter M. Pryciak

University of Massachusetts Medical School Faculty Publications

The MAP kinase cascade is a ubiquitous eukaryotic signaling module that can be controlled by a diverse group of scaffold proteins. In budding yeast, activation of the mating MAP kinase cascade involves regulated membrane recruitment of the archetypal scaffold protein Ste5. This event promotes activation of the first kinase, but it also enhances subsequent signal propagation through the remainder of the cascade. By studying this latter effect, we find that membrane recruitment promotes signaling in trans between kinases on separate Ste5 molecules. First, trans signaling requires all Ste5 domains that mediate membrane recruitment, including both protein-binding and membrane-binding domains. Second ...


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 ...


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 ...


Smooth Muscle Cell-Specific Tmem16a Deletion Does Not Alter Ca2+ Signaling, Uterine Contraction, Gestation Length Or Litter Size In Micedagger, Mingzi Qu, Ping Lu, Karl D. Bellve, Kevin E. Fogarty, Lawrence M. Lifshitz, Fangxiong Shi, Ronghua Zhuge Jun 2019

Smooth Muscle Cell-Specific Tmem16a Deletion Does Not Alter Ca2+ Signaling, Uterine Contraction, Gestation Length Or Litter Size In Micedagger, Mingzi Qu, Ping Lu, Karl D. Bellve, Kevin E. Fogarty, Lawrence M. Lifshitz, Fangxiong Shi, Ronghua Zhuge

Program in Molecular Medicine Publications and Presentations

Ion channels in myometrial cells play critical roles in spontaneous and agonist-induced uterine contraction during the menstrual cycle, pregnancy maintenance and parturition; thus identifying the genes of ion channels in these cells and determining their roles are essential to understanding the biology of reproduction. Previous studies with in vitro functional and pharmacological approaches have produced controversial results regarding the presence and role of TMEM16A Ca2+-activated Cl- channels in myometrial cells. To unambiguously determine the function of this channel in these cells, we employed a genetic approach by using smooth muscle cell-specific TMEM16A deletion (i.e. TMEM16ASMKO) mice. We found ...


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 ...


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 ...