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2014

University of Massachusetts Medical School

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Articles 1 - 30 of 51

Full-Text Articles in Cell Biology

Higher-Order Unfolding Of Peri/Centric Satellite Heterochromatin Is An Early And Consistent Event In Cell Senescence: A Dissertation, Eric C. Swanson Dec 2014

Higher-Order Unfolding Of Peri/Centric Satellite Heterochromatin Is An Early And Consistent Event In Cell Senescence: A Dissertation, Eric C. Swanson

GSBS Dissertations and Theses

Cellular senescence is thought to play an essential role in many biological functions including tumor suppression and organismal aging. Senescent cells, which are permanently removed from the cell cycle, can be found both in vivo in many different tissue types and in vitro within cultures of non-immortalized cells. Despite their inability to proliferate, these cells persist and remain metabolically active for indefinite periods of time. This physiologic process occurs in response to a variety of cellular insults including oxidative stress, shortened telomeres, constitutive oncogene expression, and DNA damage, and can be initiated by upregulation of one of the two known ...


A Calcium-Dependent Protease As A Potential Therapeutic Target For Wolfram Syndrome, Simin Lu, Clay F. Semenkovich, Peter A. Greer, Fumihiko Urano Dec 2014

A Calcium-Dependent Protease As A Potential Therapeutic Target For Wolfram Syndrome, Simin Lu, Clay F. Semenkovich, Peter A. Greer, Fumihiko Urano

GSBS Student Publications

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced ...


Optimization Of Transcription Factor Binding Map Accuracy Utilizing Knockout-Mouse Models, Wolfgang Krebs, Susanne V. Schmidt, Alon Goren, Dominic De Nardo, Larisa Labzin, Anton Bovier, Thomas Ulas, Heidi Theis, Michael Kraut, Eicke Latz, Marc Beyer, Joachim L. Schultze Dec 2014

Optimization Of Transcription Factor Binding Map Accuracy Utilizing Knockout-Mouse Models, Wolfgang Krebs, Susanne V. Schmidt, Alon Goren, Dominic De Nardo, Larisa Labzin, Anton Bovier, Thomas Ulas, Heidi Theis, Michael Kraut, Eicke Latz, Marc Beyer, Joachim L. Schultze

Open Access Articles

Genome-wide assessment of protein-DNA interaction by chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) is a key technology for studying transcription factor (TF) localization and regulation of gene expression. Signal-to-noise-ratio and signal specificity in ChIP-seq studies depend on many variables, including antibody affinity and specificity. Thus far, efforts to improve antibody reagents for ChIP-seq experiments have focused mainly on generating higher quality antibodies. Here we introduce KOIN (knockout implemented normalization) as a novel strategy to increase signal specificity and reduce noise by using TF knockout mice as a critical control for ChIP-seq data experiments. Additionally, KOIN can identify 'hyper ChIPable ...


Two Ways To Fold The Genome During The Cell Cycle: Insights Obtained With Chromosome Conformation Capture, Job Dekker Nov 2014

Two Ways To Fold The Genome During The Cell Cycle: Insights Obtained With Chromosome Conformation Capture, Job Dekker

Open Access Articles

Genetic and epigenetic inheritance through mitosis is critical for dividing cells to maintain their state. This process occurs in the context of large-scale re-organization of chromosome conformation during prophase leading to the formation of mitotic chromosomes, and during the reformation of the interphase nucleus during telophase and early G1. This review highlights how recent studies over the last 5 years employing chromosome conformation capture combined with classical models of chromosome organization based on decades of microscopic observations, are providing new insights into the three-dimensional organization of chromatin inside the interphase nucleus and within mitotic chromosomes. One striking observation is that ...


Amphiphilic Degradable Polymer/Hydroxyapatite Composites As Smart Bone Tissue Engineering Scaffolds: A Dissertation, Artem B. Kutikov Nov 2014

Amphiphilic Degradable Polymer/Hydroxyapatite Composites As Smart Bone Tissue Engineering Scaffolds: A Dissertation, Artem B. Kutikov

GSBS Dissertations and Theses

Over 600,000 bone-grafting operations are performed each year in the United States. The majority of the bone used for these surgeries comes from autografts that are limited in quantity or allografts with high failure rates. Current synthetic bone grafting materials have poor mechanical properties, handling characteristics, and bioactivity. The goal of this dissertation was to develop a clinically translatable bone tissue engineering scaffold with improved handling characteristics, bioactivity, and smart delivery modalities. We hypothesized that this could be achieved through the rational selection of Food and Drug Administration (FDA) approved materials that blend favorably with hydroxyapatite (HA), the principle ...


Quantitative Analysis Of App Axonal Transport In Neurons: Role Of Jip1 In Enhanced App Anterograde Transport, Kyoko Chiba, Masahiko Araseki, Keisuke Nozawa, Keiko Furukori, Yoichi Araki, Takahide Matsushima, Tadashi Nakaya, Saori Hata, Yuhki Saito, Seiichi Uchida, Yasushi Okada, Angus C. Nairn, Roger J. Davis, Tohru Yamamoto, Masataka Kinjo, Hidenori Taru, Toshiharu Suzuki Nov 2014

Quantitative Analysis Of App Axonal Transport In Neurons: Role Of Jip1 In Enhanced App Anterograde Transport, Kyoko Chiba, Masahiko Araseki, Keisuke Nozawa, Keiko Furukori, Yoichi Araki, Takahide Matsushima, Tadashi Nakaya, Saori Hata, Yuhki Saito, Seiichi Uchida, Yasushi Okada, Angus C. Nairn, Roger J. Davis, Tohru Yamamoto, Masataka Kinjo, Hidenori Taru, Toshiharu Suzuki

Davis Lab Publications

Alzheimer's beta-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity ( approximately 2.7 mum/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity ( approximately 1.83 mum/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b ...


Human Breast Progenitor Cell Numbers Are Regulated By Wnt And Tbx3, Lisa M. Arendt, Jessica St. Laurent, Ania Wronski, Silvia Caballero, Stephen Lyle, Stephen P. Naber, Charlotte Kuperwasser Oct 2014

Human Breast Progenitor Cell Numbers Are Regulated By Wnt And Tbx3, Lisa M. Arendt, Jessica St. Laurent, Ania Wronski, Silvia Caballero, Stephen Lyle, Stephen P. Naber, Charlotte Kuperwasser

Open Access Articles

BACKGROUND: Although human breast development is mediated by hormonal and non-hormonal means, the mechanisms that regulate breast progenitor cell activity remain to be clarified. This limited understanding of breast progenitor cells has been due in part to the lack of appropriate model systems to detect and characterize their properties.

METHODS: To examine the effects of WNT signaling and TBX3 expression on progenitor activity in the breast, primary human mammary epithelial cells (MEC) were isolated from reduction mammoplasty tissues and transduced with lentivirus to overexpress WNT1 or TBX3 or reduce expression of their cognate receptors using shRNA. Changes in progenitor activity ...


Reassessment Of The Role Of Tsc, Mtorc1 And Micrornas In Amino Acids-Meditated Translational Control Of Top Mrnas, Ilona Patursky-Polischuk, Judith Kasir, Rachel Miloslavski, Zvi Hayouka, Mirit Hausner-Hanochi, Miri Stolovich-Rain, Pinchas Tsukerman, Moshe Biton, Rajini R. Mudhasani, Stephen N. Jones, Oded Meyuhas Oct 2014

Reassessment Of The Role Of Tsc, Mtorc1 And Micrornas In Amino Acids-Meditated Translational Control Of Top Mrnas, Ilona Patursky-Polischuk, Judith Kasir, Rachel Miloslavski, Zvi Hayouka, Mirit Hausner-Hanochi, Miri Stolovich-Rain, Pinchas Tsukerman, Moshe Biton, Rajini R. Mudhasani, Stephen N. Jones, Oded Meyuhas

Open Access Articles

TOP mRNAs encode components of the translational apparatus, and repression of their translation comprises one mechanism, by which cells encountering amino acid deprivation downregulate the biosynthesis of the protein synthesis machinery. This mode of regulation involves TSC as knockout of TSC1 or TSC2 rescued TOP mRNAs translation in amino acid-starved cells. The involvement of mTOR in translational control of TOP mRNAs is demonstrated by the ability of constitutively active mTOR to relieve the translational repression of TOP mRNA upon amino acid deprivation. Consistently, knockdown of this kinase as well as its inhibition by pharmacological means blocked amino acid-induced translational activation ...


Regulation Of Cdk1 Activity During The G1/S Transition In S. Cerevisiae Through Specific Cyclin-Substrate Docking: A Dissertation, Samyabrata Bhaduri Oct 2014

Regulation Of Cdk1 Activity During The G1/S Transition In S. Cerevisiae Through Specific Cyclin-Substrate Docking: A Dissertation, Samyabrata Bhaduri

GSBS Dissertations and Theses

Several cell cycle events require specific forms of the cyclin-CDK complexes. It has been known for some time that cyclins not only contribute by activating the CDK but also by choosing substrates and/or specifying the location of the CDK holoenzyme. There are several examples of B-type cyclins identifying certain peptide motifs in their specific substrates through a conserved region in their structure. Such interactions were not known for the G1 class of cyclins, which are instrumental in helping the cell decide whether or not to commit to a new cell cycle, a function that is non-redundant with B-type cylins ...


Enteroendocrine Cells Support Intestinal Stem-Cell-Mediated Homeostasis In Drosophila, Alla Amcheslavsky, Wei Song, Qi Li, Yingchao Nie, Ivan Bragatto, Dominique Ferrandon, Norbert Perrimon, Y. Tony Ip Oct 2014

Enteroendocrine Cells Support Intestinal Stem-Cell-Mediated Homeostasis In Drosophila, Alla Amcheslavsky, Wei Song, Qi Li, Yingchao Nie, Ivan Bragatto, Dominique Ferrandon, Norbert Perrimon, Y. Tony Ip

UMass Center for Clinical and Translational Science Supported Publications

Intestinal stem cells in the adult Drosophila midgut are regulated by growth factors produced from the surrounding niche cells including enterocytes and visceral muscle. The role of the other major cell type, the secretory enteroendocrine cells, in regulating intestinal stem cells remains unclear. We show here that newly eclosed scute loss-of-function mutant flies are completely devoid of enteroendocrine cells. These enteroendocrine cell-less flies have normal ingestion and fecundity but shorter lifespan. Moreover, in these newly eclosed mutant flies, the diet-stimulated midgut growth that depends on the insulin-like peptide 3 expression in the surrounding muscle is defective. The depletion of Tachykinin-producing ...


Modeling T Cell Receptor Recognition Of Cd1-Lipid And Mr1-Metabolite Complexes, Brian G. Pierce, Thom Vreven, Zhiping Weng Sep 2014

Modeling T Cell Receptor Recognition Of Cd1-Lipid And Mr1-Metabolite Complexes, Brian G. Pierce, Thom Vreven, Zhiping Weng

Open Access Articles

BACKGROUND: T cell receptors (TCRs) can recognize diverse lipid and metabolite antigens presented by MHC-like molecules CD1 and MR1, and the molecular basis of many of these interactions has not been determined. Here we applied our protein docking algorithm TCRFlexDock, previously developed to perform docking of TCRs to peptide-MHC (pMHC) molecules, to predict the binding of alphabeta and gammadelta TCRs to CD1 and MR1, starting with the structures of the unbound molecules.

RESULTS: Evaluating against TCR-CD1d complexes with crystal structures, we achieved near-native structures in the top 20 models for two out of four cases, and an acceptable-rated prediction for ...


Small Rnas And Argonautes Provide A Paternal Epigenetic Memory Of Germline Gene Expression To Promote Thermotolerant Male Fertility: A Dissertation, Colin C. Conine Sep 2014

Small Rnas And Argonautes Provide A Paternal Epigenetic Memory Of Germline Gene Expression To Promote Thermotolerant Male Fertility: A Dissertation, Colin C. Conine

GSBS Dissertations and Theses

During each life cycle, gametes must preserve and pass on both genetic and epigenetic information, making the germline both immortal and totipotent. In the male germline the dramatic morphological transformation of a germ cell through meiosis, into a sperm competent for fertilization, while retaining this information is an incredible example of cellular differentiation. This process of spermatogenesis is inherently thermosensitive in numerous metazoa ranging from worms to man. Here, I describe the role of two redundant AGO-class paralogs, ALG-3/4, and their small RNA cofactors, in promoting thermotolerant male fertility in Caenorhabditis elegans. alg-3/4 double mutants exhibit temperature dependent ...


A Separable Domain Of The P150 Subunit Of Human Chromatin Assembly Factor-1 Promotes Protein And Chromosome Associations With Nucleoli, Corey L. Smith, Timothy D. Matheson, Daniel J. Trombly, Xiaoming Sun, Eric Campeau, Xuemei Han, John R. Yates Iii, Paul D. Kaufman Sep 2014

A Separable Domain Of The P150 Subunit Of Human Chromatin Assembly Factor-1 Promotes Protein And Chromosome Associations With Nucleoli, Corey L. Smith, Timothy D. Matheson, Daniel J. Trombly, Xiaoming Sun, Eric Campeau, Xuemei Han, John R. Yates Iii, Paul D. Kaufman

Program in Gene Function and Expression Publications and Presentations

Chromatin Assembly Factor-1 (CAF-1) is a three-subunit protein complex conserved throughout eukaryotes that deposits histones during DNA synthesis. Here, we present a novel role for the human p150 subunit in regulating nucleolar macromolecular interactions. Acute depletion of p150 causes redistribution of multiple nucleolar proteins and reduces nucleolar association with several repetitive element-containing loci. Notably, a point mutation in a SUMO-interacting motif (SIM) within p150 abolishes nucleolar associations, whereas PCNA or HP1 interaction sites within p150 are not required for these interactions. Additionally, acute depletion of SUMO-2 or the SUMO E2 ligase Ubc9 reduces alpha-satellite DNA association with nucleoli. The nucleolar ...


Tlr Sorting By Rab11 Endosomes Maintains Intestinal Epithelial-Microbial Homeostasis, Shiyan Yu, Yingchao Nie, Y. Tony Ip, Nan Gao Sep 2014

Tlr Sorting By Rab11 Endosomes Maintains Intestinal Epithelial-Microbial Homeostasis, Shiyan Yu, Yingchao Nie, Y. Tony Ip, Nan Gao

UMass Center for Clinical and Translational Science Supported Publications

Compartmentalization of Toll-like receptors (TLRs) in intestinal epithelial cells (IECs) regulates distinct immune responses to microbes; however, the specific cellular machinery that controls this mechanism has not been fully identified. Here we provide genetic evidences that the recycling endosomal compartment in enterocytes maintains a homeostatic TLR9 intracellular distribution, supporting mucosal tolerance to normal microbiota. Genetic ablation of a recycling endosome resident small GTPase, Rab11a, a gene adjacent to a Crohn's disease risk locus, in mouse IECs and in Drosophila midgut caused epithelial cell-intrinsic cytokine production, inflammatory bowel phenotype, and early mortality. Unlike wild-type controls, germ-free Rab11a-deficient mouse intestines failed ...


Evaluation Of The Contribution Of Multiple Damps And Damp Receptors In Cell Death-Induced Sterile Inflammatory Responses, Hiroshi Kataoka, Hajime Kono, Zubin Patel, Kenneth L. Rock Aug 2014

Evaluation Of The Contribution Of Multiple Damps And Damp Receptors In Cell Death-Induced Sterile Inflammatory Responses, Hiroshi Kataoka, Hajime Kono, Zubin Patel, Kenneth L. Rock

Open Access Articles

When cells die by necrosis in vivo they stimulate an inflammatory response. It is thought that this response is triggered when the injured cells expose proinflammatory molecules, collectively referred to as damage associated molecular patterns (DAMPs), which are recognized by cells or soluble molecules of the innate or adaptive immune system. Several putative DAMPs and/or their receptors have been identified, but whether and how much they participate in responses in vivo is incompletely understood, and they have not previously been compared side-by-side in the same models. This study focuses on evaluating the contribution of multiple mechanisms that have been ...


A System For Genome-Wide Histone Variant Dynamics In Es Cells Reveals Dynamic Macroh2a2 Replacement At Promoters, Ozlem Yildirim, Jui-Hung Hung, Ryan J. Cedeno, Zhiping Weng, Christopher J. Lengner, Oliver J. Rando Aug 2014

A System For Genome-Wide Histone Variant Dynamics In Es Cells Reveals Dynamic Macroh2a2 Replacement At Promoters, Ozlem Yildirim, Jui-Hung Hung, Ryan J. Cedeno, Zhiping Weng, Christopher J. Lengner, Oliver J. Rando

Open Access Articles

Dynamic exchange of a subset of nucleosomes in vivo plays important roles in epigenetic inheritance of chromatin states, chromatin insulator function, chromosome folding, and the maintenance of the pluripotent state of embryonic stem cells. Here, we extend a pulse-chase strategy for carrying out genome-wide measurements of histone dynamics to several histone variants in murine embryonic stem cells and somatic tissues, recapitulating expected characteristics of the well characterized H3.3 histone variant. We extended this system to the less-studied MacroH2A2 variant, commonly described as a "repressive" histone variant whose accumulation in chromatin is thought to fix the epigenetic state of differentiated ...


Hsa-Mir-30c Promotes The Invasive Phenotype Of Metastatic Breast Cancer Cells By Targeting Nov/Ccn3, Jason R. Dobson, Hanna Taipaleenmaki, Yu-Jie Hu, Deli Hong, Andre J. Van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian, Jitesh Pratap Aug 2014

Hsa-Mir-30c Promotes The Invasive Phenotype Of Metastatic Breast Cancer Cells By Targeting Nov/Ccn3, Jason R. Dobson, Hanna Taipaleenmaki, Yu-Jie Hu, Deli Hong, Andre J. Van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian, Jitesh Pratap

Open Access Articles

BACKGROUND: For treatment and prevention of metastatic disease, one of the premier challenges is the identification of pathways and proteins to target for clinical intervention. Micro RNAs (miRNAs) are short, non-coding RNAs, which regulate cellular activities by either mRNA degradation or translational inhibition. Our studies focused on the invasive properties of hsa-mir30c based on its high expression in MDA-MB-231 metastatic cells and our bioinformatic analysis of the Cancer Genome Atlas that identified aberrant hsa-mir-30c to be associated with poor survival.

METHODS: Contributions of hsa-mir-30c to breast cancer cell invasion were examined by Matrigel invasion transwell assays following modulation of hsa-mir-30c ...


Quantitative Proteomic Analysis Reveals Posttranslational Responses To Aneuploidy In Yeast, Noah Dephoure, Sunyoung Hwang, Ciara O'Sullivan, Stacie E. Dodgson, Steven P. Gygi, Angelika Amon, Eduardo M. Torres Jul 2014

Quantitative Proteomic Analysis Reveals Posttranslational Responses To Aneuploidy In Yeast, Noah Dephoure, Sunyoung Hwang, Ciara O'Sullivan, Stacie E. Dodgson, Steven P. Gygi, Angelika Amon, Eduardo M. Torres

Program in Gene Function and Expression Publications and Presentations

Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by aneuploidy are not well characterized. Here, we examined the consequences of aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our proteomic analyses further revealed a novel aneuploidy-associated protein expression signature characteristic of altered metabolism and redox homeostasis. Indeed aneuploid cells harbor increased levels of reactive ...


Drosophila Sirt2/Mammalian Sirt3 Deacetylates Atp Synthase Beta And Regulates Complex V Activity, Motiur Rahman, Niraj K. Nirala, Alka Singh, Lihua Julie Zhu, Kaori Taguchi, Takeshi Bamba, Eiichiro Fukusaki, Leslie M. Shaw, David G. Lambright, Jairaj K. Acharya, Usha R. Acharya Jul 2014

Drosophila Sirt2/Mammalian Sirt3 Deacetylates Atp Synthase Beta And Regulates Complex V Activity, Motiur Rahman, Niraj K. Nirala, Alka Singh, Lihua Julie Zhu, Kaori Taguchi, Takeshi Bamba, Eiichiro Fukusaki, Leslie M. Shaw, David G. Lambright, Jairaj K. Acharya, Usha R. Acharya

Program in Gene Function and Expression Publications and Presentations

Adenosine triphosphate (ATP) synthase beta, the catalytic subunit of mitochondrial complex V, synthesizes ATP. We show that ATP synthase beta is deacetylated by a human nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, sirtuin 3, and its Drosophila melanogaster homologue, dSirt2. dsirt2 mutant flies displayed increased acetylation of specific Lys residues in ATP synthase beta and decreased complex V activity. Overexpression of dSirt2 increased complex V activity. Substitution of Lys 259 and Lys 480 with Arg in human ATP synthase beta, mimicking deacetylation, increased complex V activity, whereas substitution with Gln, mimicking acetylation, decreased activity. Mass spectrometry and proteomic experiments from ...


Phosphatidic Acid Phospholipase A1 Mediates Er-Golgi Transit Of A Family Of G Protein-Coupled Receptors, Govind Kunduri, Changqing Yuan, Velayoudame Parthibane, Katherine M. Nyswaner, Ritu Kanwar, Kunio Nagashima, Steven G. Britt, Nickita Mehta, Varshika Kotu, Mindy Porterfield, Michael Tiemeyer, Patrick J. Dolph, Usha Acharya, Jairaj K. Acharya Jul 2014

Phosphatidic Acid Phospholipase A1 Mediates Er-Golgi Transit Of A Family Of G Protein-Coupled Receptors, Govind Kunduri, Changqing Yuan, Velayoudame Parthibane, Katherine M. Nyswaner, Ritu Kanwar, Kunio Nagashima, Steven G. Britt, Nickita Mehta, Varshika Kotu, Mindy Porterfield, Michael Tiemeyer, Patrick J. Dolph, Usha Acharya, Jairaj K. Acharya

Program in Gene Function and Expression Publications and Presentations

The coat protein II (COPII)-coated vesicular system transports newly synthesized secretory and membrane proteins from the endoplasmic reticulum (ER) to the Golgi complex. Recruitment of cargo into COPII vesicles requires an interaction of COPII proteins either with the cargo molecules directly or with cargo receptors for anterograde trafficking. We show that cytosolic phosphatidic acid phospholipase A1 (PAPLA1) interacts with COPII protein family members and is required for the transport of Rh1 (rhodopsin 1), an N-glycosylated G protein-coupled receptor (GPCR), from the ER to the Golgi complex. In papla1 mutants, in the absence of transport to the Golgi, Rh1 is ...


Cooperative Binding Of The Outer Arm-Docking Complex Underlies The Regular Arrangement Of Outer Arm Dynein In The Axoneme, Mikito Owa, Akane Furuta, Jiro Usukura, Fumio Arisaka, Stephen M. King, George B. Witman, Ritsu Kamiya, Ken-Ichi Wakabayashi Jul 2014

Cooperative Binding Of The Outer Arm-Docking Complex Underlies The Regular Arrangement Of Outer Arm Dynein In The Axoneme, Mikito Owa, Akane Furuta, Jiro Usukura, Fumio Arisaka, Stephen M. King, George B. Witman, Ritsu Kamiya, Ken-Ichi Wakabayashi

Cell and Developmental Biology Publications

Outer arm dynein (OAD) in cilia and flagella is bound to the outer doublet microtubules every 24 nm. Periodic binding of OADs at specific sites is important for efficient cilia/flagella beating; however, the molecular mechanism that specifies OAD arrangement remains elusive. Studies using the green alga Chlamydomonas reinhardtii have shown that the OAD-docking complex (ODA-DC), a heterotrimeric complex present at the OAD base, functions as the OAD docking site on the doublet. We find that the ODA-DC has an ellipsoidal shape approximately 24 nm in length. In mutant axonemes that lack OAD but retain the ODA-DC, ODA-DC molecules are ...


Gene Expression Profiling Identifies The Zinc-Finger Protein Charlatan As A Regulator Of Intestinal Stem Cells In Drosophila, Alla Amcheslavsky, Yingchao Nie, Qi Li, Feng He, Leo Tsuda, Michele Markstein, Y. Tony Ip Jul 2014

Gene Expression Profiling Identifies The Zinc-Finger Protein Charlatan As A Regulator Of Intestinal Stem Cells In Drosophila, Alla Amcheslavsky, Yingchao Nie, Qi Li, Feng He, Leo Tsuda, Michele Markstein, Y. Tony Ip

UMass Center for Clinical and Translational Science Supported Publications

Intestinal stem cells (ISCs) in the adult Drosophila midgut can respond to tissue damage and support repair. We used genetic manipulation to increase the number of ISC-like cells in the adult midgut and performed gene expression profiling to identify potential ISC regulators. A detailed analysis of one of these potential regulators, the zinc-finger protein Charlatan, was carried out. MARCM clonal analysis and RNAi in precursor cells showed that loss of Chn function caused severe ISC division defects, including loss of EdU incorporation, phosphorylated histone 3 staining and expression of the mitotic protein Cdc2. Loss of Charlatan also led to a ...


Dicer Cooperates With P53 To Suppress Dna Damage And Skin Carcinogenesis In Mice, Stephen Lyle, Kathleen Hoover, Cansu Colpan, Zhiqing Zhu, Zdenka Matijasevic, Stephen N. Jones Jun 2014

Dicer Cooperates With P53 To Suppress Dna Damage And Skin Carcinogenesis In Mice, Stephen Lyle, Kathleen Hoover, Cansu Colpan, Zhiqing Zhu, Zdenka Matijasevic, Stephen N. Jones

University of Massachusetts Medical School Faculty Publications

Dicer is required for the maturation of microRNA, and loss of Dicer and miRNA processing has been found to alter numerous biological events during embryogenesis, including the development of mammalian skin and hair. We have previously examined the role of miRNA biogenesis in mouse embryonic fibroblasts and found that deletion of Dicer induces cell senescence regulated, in part, by the p53 tumor suppressor. Although Dicer and miRNA molecules are thought to have either oncogenic or tumor suppressing roles in various types of cancer, a role for Dicer and miRNAs in skin carcinogenesis has not been established. Here we show that ...


Hdac4 Integrates Pth And Sympathetic Signaling In Osteoblasts, Arnaud Obri, Munevver Parla. Makinistoglu, Hong Zhang, Gerard Karsenty Jun 2014

Hdac4 Integrates Pth And Sympathetic Signaling In Osteoblasts, Arnaud Obri, Munevver Parla. Makinistoglu, Hong Zhang, Gerard Karsenty

Cell and Developmental Biology Publications

Parathyroid hormone (PTH) and the sympathetic tone promote Rankl expression in osteoblasts and osteoclast differentiation by enhancing cyclic adenosine monophosphate production through an unidentified transcription factor for PTH and through ATF4 for the sympathetic tone. How two extracellular cues using the same second messenger in the same cell elicit different transcriptional events is unknown. In this paper, we show that PTH favors Rankl expression by triggering the ubiquitination of HDAC4, a class II histone deacetylase, via Smurf2. HDAC4 degradation releases MEF2c, which transactivates the Rankl promoter. Conversely, sympathetic signaling in osteoblasts favors the accumulation of HDAC4 in the nucleus and ...


To Protect Or Reject, Mary Munson Jun 2014

To Protect Or Reject, Mary Munson

Open Access Articles

A protein known for its role in dismantling faulty SNARE complexes can also help to maintain complexes that have formed properly during membrane fusion.


Activin Limits Progenitor Capability By Promoting Epithelial Cell Differentiation In The Mammary Gland, Karen A. Dunphy, Thiruppavai Chandrasekaran, Niraj Bhatt, Michelle Chen, Amy L. Roberts, Mary Hagen, D. Joseph Jerry May 2014

Activin Limits Progenitor Capability By Promoting Epithelial Cell Differentiation In The Mammary Gland, Karen A. Dunphy, Thiruppavai Chandrasekaran, Niraj Bhatt, Michelle Chen, Amy L. Roberts, Mary Hagen, D. Joseph Jerry

UMass Center for Clinical and Translational Science Research Retreat

Transforming growth factor beta (TGF-beta) and activin utilize common signaling pathways, via smad2/3 and smad4, to mediate tumor suppression by effecting cell cycle arrest and apoptosis. Differences in temporal expression patterns suggest that each cytokine has specific roles in mammary gland development. Activin is expressed during pregnancy and lactation and is required for branching and lactogenesis, implying a role in mammary gland maturation. In contrast, TGF-beta is expressed during involution during mammary gland regression and functions to re-organize the mammary epithelial content to the non-lactating state. Previously, we found that TGF-beta and activin do share common signaling pathways allowing ...


High Performance Amphiphilic Polymer/Hydroxyapatite Composite Tissue Scaffolds, Artem B. Kutikov, Jie Song May 2014

High Performance Amphiphilic Polymer/Hydroxyapatite Composite Tissue Scaffolds, Artem B. Kutikov, Jie Song

UMass Center for Clinical and Translational Science Research Retreat

There is a critical clinical need for alternatives to autograft and allograft bone for over 500,000 bone grafting operations performed each year in the United States. Current synthetic bone grafts suffer from poor handling characteristics, brittle mechanical properties, and inconsistent bioactivity. By blending a biodegradable amphiphilic polymer with hydroxyapatite (HA), the main mineral component in bone, we developed an improved synthetic bone graft. The polymer/HA composites were fabricated in both 2-D and 3-D forms by electrospinning and 3-D printing. These materials exhibited unique handling characteristics such as high tensile elasticity (>200% failure strain) and self-stiffening properties upon hydration ...


Pericyte Nf-Κb Activation Enhances Endothelial Cell Proliferation And Proangiogenic Cytokine Secretion, Katherine E. Labarbera, Robert D. Hyldahl, Sarah Witkowski May 2014

Pericyte Nf-Κb Activation Enhances Endothelial Cell Proliferation And Proangiogenic Cytokine Secretion, Katherine E. Labarbera, Robert D. Hyldahl, Sarah Witkowski

UMass Center for Clinical and Translational Science Research Retreat

Pericytes are skeletal muscle resident, multipotent stem cells that are localized to capillaries. They respond to damage through activation of nuclear-factor kappa-B (NF-κB), a transcription factor that regulates many cellular processes including inflammation. Research has shown that pericyte NF-κB activation positively affects myoblast proliferation. It is unknown how pericyte NF-κB affects signaling and proliferation of endothelial cells, an important component of muscle tissue microcirculation.

PURPOSE: To determine the effects of altered pericyte NF-κB activity on endothelial cell proliferation and identify inflammatory factors involved in this cell-cell signaling.

METHODS: Human primary pericytes were transfected with vectors designed to increase or decrease ...


Exosome-Mediated Delivery Of Rna Interference And Mirna Mimic, Fatemeh Momen-Heravi, Shashi Bala, Terence N. Bukong, Gyongyi Szabo May 2014

Exosome-Mediated Delivery Of Rna Interference And Mirna Mimic, Fatemeh Momen-Heravi, Shashi Bala, Terence N. Bukong, Gyongyi Szabo

UMass Center for Clinical and Translational Science Research Retreat

Exosomes, membranous nanovesicles, naturally carry bio-macromolecules and play pivotal roles in both physiological intercellular crosstalk and disease pathogenesis. Here, we showed that B cell-derived exosomes can function as vehicles to deliver exogenous miRNA-155 mimic or inhibitor into hepatocytes or macrophages, respectively. Stimulation of B cells significantly increased exosome production. Unlike in parental cells, baseline level of miRNA-155 was very low in exosomes derived from stimulated B cells. Exosomes loaded with a miRNA-155 mimic significantly increased miRNA-155 levels in primary mouse hepatocytes and the liver of miRNA-155 knockout mice. Treatment of RAW macrophages with miRNA-155 inhibitor loaded exosomes resulted in statistically ...


Anti-Ppkcθ (T538) Delivery Via Cell Penetrating Peptide Mimics As A Novel Treatment Of Aplastic Anemia, Emrah Ilker Ozay, Gabriela Gonzalez-Perez, Joe Torres, Gregory N. Tew, Lisa M. Minter May 2014

Anti-Ppkcθ (T538) Delivery Via Cell Penetrating Peptide Mimics As A Novel Treatment Of Aplastic Anemia, Emrah Ilker Ozay, Gabriela Gonzalez-Perez, Joe Torres, Gregory N. Tew, Lisa M. Minter

UMass Center for Clinical and Translational Science Research Retreat

The objective of this study is to deliver anti-pPKCθ (T538) into T cells (hPBMCs) by using cell penetrating peptide mimics (CPPMs) to neutralize PKCθ activity both in vitro and in vivo, with the eventual goal of treating aplastic anemia (AA). AA is an immune-mediated bone marrow failure disease caused by T helper type 1 (Th1) autoimmune responses, which destroy blood cell progenitors. It was previously reported that protein kinase C theta (PKCθ), expressed specifically in T cells, plays an important role in T cell signaling by mediating Th1 differentiation. Mice treated with Rottlerin, a pharmacological inhibitor of PKCθ, are rescued ...