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Articles 1 - 30 of 31

Full-Text Articles in Cell Biology

Cardiac Effects Of Huntington’S Disease In Murine Models, Daniel David Child Jan 2019

Cardiac Effects Of Huntington’S Disease In Murine Models, Daniel David Child

Publicly Accessible Penn Dissertations

Huntington’s disease (HD) is an autosomal dominant disease known for its severe neurologic phenotype. However, the causative protein in HD, mutant huntingtin (mHTT), is widely expressed across tissue types and may have profound consequences for peripheral organs. Notably, heart disease is the second leading cause of death in HD patients, but if or how cardiac mHTT expression causes pathology is still unknown. Here, I characterize the cardiac phenotype in two HD mouse models and show that dysregulated mTORC1 activity is a key underlying mechanism. I show that normal heart growth is limited in HD mouse models, with mass regulated ...


Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington Sep 2018

Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington

University of Massachusetts Medical School Publications

Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA-sequencing and ChIP studies show that the expression of microRNAs let-7c-2, miR-23b and miR-29c is suppressed by histone ...


Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Kamal Rahmouni, Donald A. Morgan, Michael P. Czech May 2018

Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Kamal Rahmouni, Donald A. Morgan, Michael P. Czech

University of Massachusetts Medical School Faculty Publications

White adipose tissue (WAT) secretes factors to communicate with other metabolic organs to maintain energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) causes expansion of sympathetic neurons within white adipose tissue (WAT) and the appearance of beige adipocytes. Here we report evidence that white adipocyte DNL activity is also coupled to neuronal regulation and thermogenesis in brown adipose tissue (BAT). Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. In ...


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

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

Molecular and Cellular Biochemistry Faculty Publications

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


A Naturally Generated Decoy Of The Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance In Tumors, Nikhil Hebbar, Ravshan Burikhanov, Nidhi Shukla, Shirley Qiu, Yanming Zhao, Kojo S. J. Elenitoba-Johnson, Vivek M. Rangnekar Aug 2017

A Naturally Generated Decoy Of The Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance In Tumors, Nikhil Hebbar, Ravshan Burikhanov, Nidhi Shukla, Shirley Qiu, Yanming Zhao, Kojo S. J. Elenitoba-Johnson, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA ...


Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair Mar 2017

Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced ...


Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang Nov 2016

Intraflagellar Transport Protein Ift20 Is Essential For Male Fertility And Spermiogenesis In Mice, Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E. Teves, Hong Liu, Jerome F. Strauss 3rd, Gregory J. Pazour, James A. Foster, Rex A. Hess, Zhibing Zhang

University of Massachusetts Medical School Faculty Publications

Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules. Electron microscopy revealed increased cytoplasmic vesicles, fiber-like structures, abnormal accumulation of mitochondria and a decrease in mature lysosomes. The few developed sperm had ...


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

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

Markey Cancer Center Faculty Publications

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


The Nuclear Factor Of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is A Repressor Of Chondrogenesis, Ann M. Ranger, Louis C. Gerstenfeld, Jinxi Wang, Tamiyo Kon, Hyunsu Bae, Ellen M. Gravallese, Melvin J. Glimcher, Laurie H. Glimcher Apr 2015

The Nuclear Factor Of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is A Repressor Of Chondrogenesis, Ann M. Ranger, Louis C. Gerstenfeld, Jinxi Wang, Tamiyo Kon, Hyunsu Bae, Ellen M. Gravallese, Melvin J. Glimcher, Laurie H. Glimcher

Ellen M. Gravallese

Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate ...


A Lipopolysaccharide-Induced Dna-Binding Protein For A Class Ii Gene In B Cells Is Distinct From Nf-Kappa B, Ellen M. Gravallese, Mark R. Boothby, Cynthia M. Smas, Laurie H. Glimcher Apr 2015

A Lipopolysaccharide-Induced Dna-Binding Protein For A Class Ii Gene In B Cells Is Distinct From Nf-Kappa B, Ellen M. Gravallese, Mark R. Boothby, Cynthia M. Smas, Laurie H. Glimcher

Ellen M. Gravallese

Class II (Ia) major histocompatibility complex molecules are cell surface proteins normally expressed by a limited subset of cells of the immune system. These molecules regulate the activation of T cells and are required for the presentation of antigens and the initiation of immune responses. The expression of Ia in B cells is determined by both the developmental stage of the B cell and by certain external stimuli. It has been demonstrated previously that treatment of B cells with lipopolysaccharide (LPS) results in increased surface expression of Ia protein. However, we have confirmed that LPS treatment results in a significant ...


A Mutation In The Mouse Chd2 Chromatin Remodeling Enzyme Results In A Complex Renal Phenotype, Concetta Marfella, Nils Henninger, Scott Leblanc, Namrata Krishnan, David Garlick, Lawrence Holzman, Anthony Imbalzano Apr 2015

A Mutation In The Mouse Chd2 Chromatin Remodeling Enzyme Results In A Complex Renal Phenotype, Concetta Marfella, Nils Henninger, Scott Leblanc, Namrata Krishnan, David Garlick, Lawrence Holzman, Anthony Imbalzano

Nils Henninger

BACKGROUND AND AIMS: Glomerular diseases are the third leading cause of kidney failure worldwide, behind only diabetes and hypertension. The molecular mechanisms underlying the cause of glomerular diseases are still largely unknown. The identification and characterization of new molecules associated with glomerular function should provide new insights into understanding the diverse group of glomerular diseases. The Chd2 protein belongs to a family of enzymes involved in ATP-dependent chromatin remodeling, suggesting that it likely functions as an epigenetic regulator of gene expression via the modification of chromatin structure. METHODS: In this study, we present a detailed histomorphologic characterization of mice containing ...


Nuclear Pore Component Nup98 Is A Potential Tumor Suppressor And Regulates Posttranscriptional Expression Of Select P53 Target Genes, Stephan Singer, Ruiying Zhao, Anthony M. Barsotti, Anette Ouwehand, Mina Fazollahi, Elias Coutavas, Kai Breuhahn, Olaf Neumann, Thomas Longerich, Tobias Pusterla, Maureen A. Powers, Keith M. Giles, Peter J. Leedman, Jochen Hess, David Grunwald, Harmen J. Bussemaker, Robert H. Singer, Peter Schirmacher, Carol Prives Nov 2014

Nuclear Pore Component Nup98 Is A Potential Tumor Suppressor And Regulates Posttranscriptional Expression Of Select P53 Target Genes, Stephan Singer, Ruiying Zhao, Anthony M. Barsotti, Anette Ouwehand, Mina Fazollahi, Elias Coutavas, Kai Breuhahn, Olaf Neumann, Thomas Longerich, Tobias Pusterla, Maureen A. Powers, Keith M. Giles, Peter J. Leedman, Jochen Hess, David Grunwald, Harmen J. Bussemaker, Robert H. Singer, Peter Schirmacher, Carol Prives

David Grünwald

The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3sigma) to be similarly regulated by Nup98. The ...


Id2 Complexes With The Snag Domain Of Snai1 Inhibiting Snai1-Mediated Repression Of Integrin Beta4, Cheng Chang, Xiaofang Yang, Bryan Pursell, Arthur M. Mercurio Nov 2014

Id2 Complexes With The Snag Domain Of Snai1 Inhibiting Snai1-Mediated Repression Of Integrin Beta4, Cheng Chang, Xiaofang Yang, Bryan Pursell, Arthur M. Mercurio

Arthur M. Mercurio

The epithelial-mesenchymal transition (EMT) is a fundamental process that underlies development and cancer. Although the EMT involves alterations in the expression of specific integrins that mediate stable adhesion to the basement membrane, such as alpha6beta4, the mechanisms involved are poorly understood. Here, we report that Snai1 inhibits beta4 transcription by increasing repressive histone modification (trimethylation of histone H3 at K27 [H3K27Me3]). Surprisingly, Snai1 is expressed and localized in the nucleus in epithelial cells, but it does not repress beta4. We resolved this paradox by discovering that Id2 complexes with the SNAG domain of Snai1 on the beta4 promoter and constrains ...


Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo Sep 2014

Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo

Katherine A. Fitzgerald

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis ...


Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo Sep 2014

Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo

Gyongyi Szabo

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis ...


Pubertal And Adult Leydig Cell Function In Mullerian Inhibiting Substance-Deficient Mice, Xiufeng Wu, Ramamani Arumugam, Stephen Baker, Mary Lee Sep 2014

Pubertal And Adult Leydig Cell Function In Mullerian Inhibiting Substance-Deficient Mice, Xiufeng Wu, Ramamani Arumugam, Stephen Baker, Mary Lee

Mary M. Lee

Mullerian inhibiting substance (MIS) causes Mullerian duct regression during sexual differentiation and regulates postnatal Leydig cell development. MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperplasia, but their circulating androgen concentrations are reportedly unaltered. We compared reproductive hormone profiles, androgen biosynthesis, and the expression of key steroidogenic and metabolic enzymes in MIS-KO and wild-type (WT) mice at puberty (36 d) and sexual maturity (60 d). In pubertal animals, basal testosterone and LH concentrations in plasma were lower in MIS-KO than WT mice, whereas human chorionic gonadotropin-stimulated testosterone concentrations were similar. In adults, basal LH, and both ...


P19ink4d And P18ink4c Cyclin-Dependent Kinase Inhibitors In The Male Reproductive Axis, Gregory Buchold, Patricia Magyar, Ramamani Arumugam, Mary Lee, Deborah O'Brien Sep 2014

P19ink4d And P18ink4c Cyclin-Dependent Kinase Inhibitors In The Male Reproductive Axis, Gregory Buchold, Patricia Magyar, Ramamani Arumugam, Mary Lee, Deborah O'Brien

Mary M. Lee

The loss of the cyclin-dependent kinase inhibitors (CKIs) p18(Ink4c) and p19(Ink4d) leads to male reproductive defects (Franklin et al., 1998. Genes Dev 12: 2899-2911; Zindy et al., 2000. Mol Cell Biol 20: 372-378; Zindy et al., 2001. Mol Cell Biol 21: 3244-3255). In order to assess whether these inhibitors directly or indirectly affect male germ cell differentiation, we examined the expression of p18(Ink4c) and p19(Ink4d) in spermatogenic and supporting cells in the testis and in pituitary gonadotropes. Both p18(Ink4c) and p19(Ink4d) are most abundant in the testis after 18 days of age and are ...


Androgen Profiles During Pubertal Leydig Cell Development In Mice, Xiufeng Wu, Ramamani Arumugam, Ningning Zhang, Mary Lee Sep 2014

Androgen Profiles During Pubertal Leydig Cell Development In Mice, Xiufeng Wu, Ramamani Arumugam, Ningning Zhang, Mary Lee

Mary M. Lee

Postnatal Leydig cell (LC) development in mice has been assumed empirically to resemble that of rats, which have characteristic hormonal profiles at well-defined maturational stages. To characterize the changes in LC function and gene expression in mice, we examined reproductive hormone expression from birth to 180 days, and quantified in vivo and in vitro production of androgens during sexual maturation. Although the overall plasma androgen and LH profiles from birth through puberty were comparable to that of rats, the timing of developmental changes in androgen production and steroidogenic capacity of isolated LCs differed. In mice, onset of androgen biosynthetic capacity ...


Effect Of E. Coli Endotoxin On Mammalian Cell Growth And Recombinant Protein Production, J. Epstein, Mary Lee, C. Kelly, Patricia Donahoe Sep 2014

Effect Of E. Coli Endotoxin On Mammalian Cell Growth And Recombinant Protein Production, J. Epstein, Mary Lee, C. Kelly, Patricia Donahoe

Mary M. Lee

No abstract provided.


Stomatin-Like Protein 2 Deficiency In T Cells Is Associated With Altered Mitochondrial Respiration And Defective Cd4+ T Cell Responses., Darah A Christie, Panagiotis Mitsopoulos, Julianna Blagih, Stanley D Dunn, Julie St-Pierre, Russell G Jones, Grant M Hatch, Joaquín Madrenas Sep 2013

Stomatin-Like Protein 2 Deficiency In T Cells Is Associated With Altered Mitochondrial Respiration And Defective Cd4+ T Cell Responses., Darah A Christie, Panagiotis Mitsopoulos, Julianna Blagih, Stanley D Dunn, Julie St-Pierre, Russell G Jones, Grant M Hatch, Joaquín Madrenas

Stanley D Dunn

Stomatin-like protein 2 (SLP-2) is a mostly mitochondrial protein that regulates mitochondrial biogenesis and function and modulates T cell activation. To determine the mechanism of action of SLP-2, we generated T cell-specific SLP-2-deficient mice. These mice had normal numbers of thymocytes and T cells in the periphery. However, conventional SLP-2-deficient T cells had a posttranscriptional defect in IL-2 production in response to TCR ligation, and this translated into reduced CD4(+) T cell responses. SLP-2 deficiency was associated with impaired cardiolipin compartmentalization in mitochondrial membranes, decreased levels of the NADH dehydrogenase (ubiquinone) iron-sulfur protein 3, NADH dehydrogenase (ubiquinone) 1β subcomplex subunit ...


Abnormal Trafficking Of Endogenously Expressed Bmpr2 Mutant Allelic Products In Patients With Heritable Pulmonary Arterial Hypertension, Andrea L Frump, Jonathan W. Lowery Ph.D., Rizwan Hamid, Eric D Austin, Mark De Caestecker Jan 2013

Abnormal Trafficking Of Endogenously Expressed Bmpr2 Mutant Allelic Products In Patients With Heritable Pulmonary Arterial Hypertension, Andrea L Frump, Jonathan W. Lowery Ph.D., Rizwan Hamid, Eric D Austin, Mark De Caestecker

Faculty Publications and Research

More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 ...


Pcdp1 Is A Central Apparatus Protein That Binds Ca2+-Calmodulin And Regulates Ciliary Motility, Christen G. Dipetrillo, Elizabeth F. Smith Apr 2010

Pcdp1 Is A Central Apparatus Protein That Binds Ca2+-Calmodulin And Regulates Ciliary Motility, Christen G. Dipetrillo, Elizabeth F. Smith

Open Dartmouth: Faculty Open Access Scholarship

For all motile eukaryotic cilia and flagella, beating is regulated by changes in intraciliary calcium concentration. Although the mechanism for calcium regulation is not understood, numerous studies have shown that calmodulin (CaM) is a key axonemal calcium sensor. Using anti-CaM antibodies and Chlamydomonas reinhardtii axonemal extracts, we precipitated a complex that includes four polypeptides and that specifically interacts with CaM in high [Ca2+]. One of the complex members, FAP221, is an orthologue of mammalian Pcdp1 (primary ciliary dyskinesia protein 1). Both FAP221 and mammalian Pcdp1 specifically bind CaM in high [Ca2+]. Reduced expression of Pcdp1 complex members in ...


Supervillin Slows Cell Spreading By Facilitating Myosin Ii Activation At The Cell Periphery, Norio Takizawa, Reiko Ikebe, Mitsuo Ikebe, Elizabeth J. Luna Jan 2010

Supervillin Slows Cell Spreading By Facilitating Myosin Ii Activation At The Cell Periphery, Norio Takizawa, Reiko Ikebe, Mitsuo Ikebe, Elizabeth J. Luna

Elizabeth J. Luna

During cell migration, myosin II modulates adhesion, cell protrusion and actin organization at the leading edge. We show that an F-actin- and membrane-associated scaffolding protein, called supervillin (SV, p205), binds directly to the subfragment 2 domains of nonmuscle myosin IIA and myosin IIB and to the N-terminus of the long form of myosin light chain kinase (L-MLCK). SV inhibits cell spreading via an MLCK- and myosin II-dependent mechanism. Overexpression of SV reduces the rate of cell spreading, and RNAi-mediated knockdown of endogenous SV increases it. Endogenous and EGFP-tagged SV colocalize with, and enhance the formation of, cortical bundles of F-actin ...


Mtorc1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis Via Increased Hexokinase Ii And Glut1 Expression, Sustained Mcl-1 Expression, And Glycogen Synthase Kinase 3Β Inhibition, Prashanth T. Bhaskar, Veronique Nogueira, Krushna C. Patra, Sang-Min Jeon, Youngkyu Park, R. Brooks Robey, Nissim Hay Sep 2009

Mtorc1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis Via Increased Hexokinase Ii And Glut1 Expression, Sustained Mcl-1 Expression, And Glycogen Synthase Kinase 3Β Inhibition, Prashanth T. Bhaskar, Veronique Nogueira, Krushna C. Patra, Sang-Min Jeon, Youngkyu Park, R. Brooks Robey, Nissim Hay

Open Dartmouth: Faculty Open Access Scholarship

The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1α (HIF1α) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1α abundance in these cells is attributed ...


Merlin Differs From Moesin In Binding To F-Actin And In Its Intra- And Intermolecular Interactions, L. Huang, E. Ichimaru, Kersi Pestonjamasp, X. Cui, H. Nakamura, G. Lo, F. Lin, Elizabeth Luna, H. Furthmayr Mar 2008

Merlin Differs From Moesin In Binding To F-Actin And In Its Intra- And Intermolecular Interactions, L. Huang, E. Ichimaru, Kersi Pestonjamasp, X. Cui, H. Nakamura, G. Lo, F. Lin, Elizabeth Luna, H. Furthmayr

Elizabeth J. Luna

The neurofibromatosis type 2 (NF2) tumor suppressor gene encodes merlin, a protein with homology to the cell membrane/F-actin linking proteins, moesin, ezrin and radixin. Unlike these closely related proteins, merlin lacks a C-terminal F-actin binding site detectable by actin blot overlays, and the GFP-tagged merlin C-terminal domain co-distributes with neither stress fibers nor cortical actin in NIH3T3 cells. Merlin also differs from the other three proteins in its inter- and intramolecular domain interactions, as shown by in vitro binding and yeast two-hybrid assays. As is true for ezrin, moesin and radixin, the N- and C-terminal domains of merlin type ...


Supervillin Modulation Of Focal Adhesions Involving Trip6/Zrp-1, Norio Takizawa, Tara C. Smith, Thomas Nebl, Jessica Lynn Crowley, Stephen J. Palmieri, Lawrence M. Lifshitz, Anka G. Ehrhardt, Laura M. Hoffman, Mary C. Beckerle, Elizabeth J. Luna Mar 2008

Supervillin Modulation Of Focal Adhesions Involving Trip6/Zrp-1, Norio Takizawa, Tara C. Smith, Thomas Nebl, Jessica Lynn Crowley, Stephen J. Palmieri, Lawrence M. Lifshitz, Anka G. Ehrhardt, Laura M. Hoffman, Mary C. Beckerle, Elizabeth J. Luna

Elizabeth J. Luna

Cell-substrate contacts, called focal adhesions (FAs), are dynamic in rapidly moving cells. We show that supervillin (SV)--a peripheral membrane protein that binds myosin II and F-actin in such cells--negatively regulates stress fibers, FAs, and cell-substrate adhesion. The major FA regulatory sequence within SV (SV342-571) binds to the LIM domains of two proteins in the zyxin family, thyroid receptor-interacting protein 6 (TRIP6) and lipoma-preferred partner (LPP), but not to zyxin itself. SV and TRIP6 colocalize within large FAs, where TRIP6 may help recruit SV. RNAi-mediated decreases in either protein increase cell adhesion to fibronectin. TRIP6 partially rescues SV effects on ...


Archvillin, A Muscle-Specific Isoform Of Supervillin, Is An Early Expressed Component Of The Costameric Membrane Skeleton, Sang W. Oh, Robert K. Pope, Kelly P. Smith, Jessica Lynn Crowley, Thomas Nebl, Jeanne B. Lawrence, Elizabeth J. Luna Mar 2008

Archvillin, A Muscle-Specific Isoform Of Supervillin, Is An Early Expressed Component Of The Costameric Membrane Skeleton, Sang W. Oh, Robert K. Pope, Kelly P. Smith, Jessica Lynn Crowley, Thomas Nebl, Jeanne B. Lawrence, Elizabeth J. Luna

Elizabeth J. Luna

The membrane skeleton protein supervillin binds tightly to both F-actin and membranes and can potentiate androgen receptor activity in non-muscle cells. We report that muscle, which constitutes the principal tissue source for supervillin sequences, contains a approximately 250 kDa isoform of supervillin that localizes within nuclei and with dystrophin at costameres, regions of F-actin membrane attachment in skeletal muscle. The gene encoding this protein, 'archvillin' (Latin, archi; Greek, archos; 'principal' or 'chief'), contains an evolutionarily conserved, muscle-specific 5' leader sequence. Archvillin cDNAs also contain four exons that encode approximately 47 kDa of additional muscle-specific protein sequence in the form of ...


Cross-Bridge Kinetics Of Cardiac Myofibrils Carrying Myopathy-Causing Mutation, Disha Dumka M.S. May 2007

Cross-Bridge Kinetics Of Cardiac Myofibrils Carrying Myopathy-Causing Mutation, Disha Dumka M.S.

Theses and Dissertations

Dumka, Disha., Cross-bridge kinetics of cardiac myofibrils carrying myopathy-causing mutation. Doctor of Philosophy (Biochemistry and Molecular Biology), May 2007, 98 pp., 8 tables, 23 illustrations, and bibliography: 102 titles. Familial hypertrophic cardiomyopathy is a disease characterized by left ventricular hypertrophy and myofibrillar disarray. It is caused by mutations in sarcomeric proteins, including the ventricular isoform of myosin regulatory light chain (RLC). We have focused on one particular mutation of RLC-substitution of glutamic acid (E) at position 22 for lysine (K). The E22k mutation is located in the RLC Ca2+ -binding site. Earlier work has demonstrated that phosphorylation and Ca2+ binding ...


Expression Of Rag2 And V(D)J Recombinase Activity Are Reduced In Aged Mice As A Result Of Changes In The Bone Marrow Microenvironment: A Dissertation, Joseph E. Labrie Iii Feb 2004

Expression Of Rag2 And V(D)J Recombinase Activity Are Reduced In Aged Mice As A Result Of Changes In The Bone Marrow Microenvironment: A Dissertation, Joseph E. Labrie Iii

GSBS Dissertations and Theses

Both humans and mice display an age-related decline in immunity. Reduced generation of mature B cells may be a contributing factor due to reduced entry of mature B cells with novel B cell receptors and specificity for pathogens into the mature B cell pool. In aged mice the numbers of B cell precursors within the bone marrow are diminished; there is a severe reduction in numbers of pre-B cells and an increase in numbers of re-circulated mature B cells. Other defects in developing B cells include reduced expression of rag1 and rag2 when measured in total bone marrow precursor populations ...


Bcma Is Essential For The Survival Of Long-Lived Bone Marrow Plasma Cells, Brian P. O'Connor, Vanitha S. Raman, Loren D. Erickson, W. James Cook, Lehn K. Weaver, Cory Ahonen, Ling-Li Lin, George Mantchev, Richard J. Bram, Randolph J. Noelle Jan 2004

Bcma Is Essential For The Survival Of Long-Lived Bone Marrow Plasma Cells, Brian P. O'Connor, Vanitha S. Raman, Loren D. Erickson, W. James Cook, Lehn K. Weaver, Cory Ahonen, Ling-Li Lin, George Mantchev, Richard J. Bram, Randolph J. Noelle

Open Dartmouth: Faculty Open Access Scholarship

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by inter- leukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this 􏰀-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival ...