Página 20 dos resultados de 45945 itens digitais encontrados em 0.057 segundos

‣ CCP1/Nna1 functions in protein turnover in mouse brain: Implications for cell death in Purkinje cell degeneration mice

BEREZNIUK, Iryna; SIRONI, Juan; CALLAWAY, Myrasol B.; CASTRO, Leandro M.; HIRATA, Izaura Y.; FERRO, Emer S.; FRICKER, Lloyd D.
Fonte: FEDERATION AMER SOC EXP BIOL Publicador: FEDERATION AMER SOC EXP BIOL
Tipo: Artigo de Revista Científica
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Purkinje cell degeneration (pcd) mice have a mutation within the gene encoding cytosolic carboxypeptidase 1 (CCP1/Nna1), which has homology to metallocarboxypeptidases. To assess the function of CCP1/Nna1, quantitative proteomics and peptidomics approaches were used to compare proteins and peptides in mutant and wild-type mice. Hundreds of peptides derived from cytosolic and mitochondrial proteins are greatly elevated in pcd mouse hypothalamus, amygdala, cortex, prefrontal cortex, and striatum. However, the major proteins detected on 2-D gel electrophoresis were present in mutant and wild-type mouse cortex and hypothalamus at comparable levels, and proteasome activity is normal in these brain regions of pcd mice, suggesting that the increase in cellular peptide levels in the pcd mice is due to reduced degradation of the peptides downstream of the proteasome. Both nondegenerating and degenerating regions of pcd mouse brain, but not wild-type mouse brain, show elevated autophagy, which can be triggered by a decrease in amino acid levels. Taken together with previous studies on CCP1/Nna1, these data suggest that CCP1/Nna1 plays a role in protein turnover by cleaving proteasome-generated peptides into amino acids and that decreased peptide turnover in the pcd mice leads to cell death.-Berezniuk...

‣ Analysis of Protein Localization and Secretory Pathway Function Using the Yeast Saccharomyces cerevisiae

Vallen, Elizabeth
Fonte: The American Society for Cell Biology Publicador: The American Society for Cell Biology
Tipo: Artigo de Revista Científica
Publicado em //2002 Português
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The isolation and characterization of mutants has been crucial in understanding a number of processes in the field of cell biology. In this exercise, students examine the effects of mutations in the secretory pathway on protein localization. Yeast strains deficient for synthesis of histidinol dehydrogenase are transformed with a plasmid encoding a chimeric protein. The chimera contains a signal sequence fused to histidinol dehydrogenase. A strain with a defect in the translocation of secretory proteins into the endoplasmic reticulum (ER) accumulates sufficient histidinol dehydrogenase in the cytoplasm to grow on media lacking histidine. In contrast, yeast proficient for secretion, or yeast with secretion defects later in the pathway, are unable to grow on media lacking histidine. Student analysis of the experimental yeast transformants and appropriate controls allows investigation into the effects of conditional defects in the secretory pathway on both cell viability and protein localization. The exercise is usually performed in a manner that allows students to execute a number of techniques common in molecular biology laboratories, including plasmid minipreps, restriction digestions, and Southern blots. Student understanding and enjoyment of the exercise was assessed by laboratory reports...

‣ Unique Impact of RB Loss on Hepatic Proliferation: TUMORIGENIC STRESSES UNCOVER DISTINCT PATHWAYS OF CELL CYCLE CONTROL

Reed, Christopher A.; Mayhew, Christopher N.; McClendon, A. Kathleen; Knudsen, Erik S.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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The retinoblastoma (RB) tumor suppressor pathway is disrupted at high frequency in hepatocellular carcinoma. However, the mechanisms through which RB modulates physiological responses in the liver remain poorly defined. Despite the well established role of RB in cell cycle control, the deletion of RB had no impact on the kinetics of cell cycle entry or the restoration of quiescence during the course of liver regeneration. Although these findings indicated compensatory effects from the RB-related proteins p107 and p130, even the dual deletion of RB with p107 or p130 failed to deregulate hepatic proliferation. Furthermore, although these findings suggested a modest role for the RB-pathway in the context of proliferative control, RB loss had striking effects on response to the genotoxic hepatocarcinogen diethylnitrosamine. With diethylnitrosamine, RB deletion resulted in inappropriate cell cycle entry that facilitated secondary genetic damage and further uncoupling of DNA replication with mitotic entry. Analysis of the mechanism underlying the differential impact of RB status on liver biology revealed that, while liver regeneration is associated with the conventional induction of cyclin D1 expression, the RB-dependent cell cycle entry...

‣ An update on the rapid advances in malaria parasite cell biology

Coppens, Isabelle; Sullivan, David J.; Prigge, Sean T.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Recent years have seen rapid advances in our understanding of malaria parasite cell biology. Some of this progress has been the result of developments in genetic techniques, advances in imaging technology, and new molecular tools. Herein, three aspects of parasite cell biology will be the topic of our focus: (i) plastid metabolism, (ii) sporozoite biology, and (iii) protein transport to and from the host erythrocyte. In each case, recent work has led to a deeper understanding of parasite biology, often at the expense of previously accepted paradigms. These studies also highlight the impediments, technical and otherwise, which will have to be overcome for continued rapid progress in these fields.

‣ Computational cell biology at the home of the helix

Ward, Jonathan J; Nédélec, Francois J
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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The Computational Cell Biology Conference, held jointly by the Cold Spring Harbor Laboratory and the Wellcome Trust, was convened in the grand surroundings of Hinxton Hall near Cambridge, England. The high quality of the research presented at the meeting confirmed that the field of computational cell biology is maturing rapidly, which mirrors the progression of cell biology from being mostly descriptive to a more quantitative discipline.

‣ Studies on the cell biology of interendothelial cell gaps

Ochoa, Cristhiaan D.; Stevens, Troy
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
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Pain, redness, heat, and swelling are hallmarks of inflammation that were recognized as early as the first century AD. Despite these early observations, the mechanisms responsible for swelling, in particular, remained an enigma for nearly two millennia. Only in the past century have scientists and physicians gained an appreciation for the role that vascular endothelium plays in controlling the exudation that is responsible for swelling. One of these mechanisms is the formation of transient gaps between adjacent endothelial cell borders. Inflammatory mediators act on endothelium to reorganize the cytoskeleton, decrease the strength of proteins that connect cells together, and induce transient gaps between endothelial cells. These gaps form a paracellular route responsible for exudation. The discovery that interendothelial cell gaps are causally linked to exudation began in the 1960s and was accompanied by significant controversy. Today, the role of gap formation in tissue edema is accepted by many, and significant scientific effort is dedicated toward developing therapeutic strategies that will prevent or reverse the endothelial cell gaps that are present during the course of inflammatory illness. Given the importance of this field in endothelial cell biology and inflammatory disease...

‣ Chemical approaches to studying stem cell biology

Li, Wenlin; Jiang, Kai; Wei, Wanguo; Shi, Yan; Ding, Sheng
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
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Stem cells, including both pluripotent stem cells and multipotent somatic stem cells, hold great potential for interrogating the mechanisms of tissue development, homeostasis and pathology, and for treating numerous devastating diseases. Establishment of in vitro platforms to faithfully maintain and precisely manipulate stem cell fates is essential to understand the basic mechanisms of stem cell biology, and to translate stem cells into regenerative medicine. Chemical approaches have recently provided a number of small molecules that can be used to control cell self-renewal, lineage differentiation, reprogramming and regeneration. These chemical modulators have been proven to be versatile tools for probing stem cell biology and manipulating cell fates toward desired outcomes. Ultimately, this strategy is promising to be a new frontier for drug development aimed at endogenous stem cell modulation.

‣ An Emerging Role for PI5P in T Cell Biology

Nunès, Jacques A.; Guittard, Geoffrey
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 02/04/2013 Português
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Phosphoinositides are critical regulators in cell biology. Phosphatidylinositol 4,5-bisphosphate, also known as PI(4,5)P2 or PIP2, was the first variety of phosphoinositide to enter in the T cell signaling scene. Phosphatidylinositol bis-phosphates are the substrates for different types of enzymes such as phospholipases C (β and γ isoforms) and phosphoinositide 3-kinases (PI3K class IA and IB) that are largely involved in signal transduction. However until recently, only a few studies highlighted phosphatidylinositol monophosphates as signaling molecules. This was mostly due to the difficulty of detection of some of these phosphoinositides, such as phosphatidylinositol 5-phosphate, also known as PI5P. Some compelling evidence argues for a role of PI5P in cell signaling and/or cell trafficking. Recently, we reported the detection of a PI5P increase upon TCR triggering. Here, we describe the current knowledge of the role of PI5P in T cell signaling. The future challenges that will be important to achieve in order to fully characterize the role of PI5P in T cell biology, will be discussed.

‣ Role of Inositol Poly-Phosphatases and Their Targets in T Cell Biology

Srivastava, Neetu; Sudan, Raki; Kerr, William Garrow
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 23/09/2013 Português
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T lymphocytes play a critical role in host defense in all anatomical sites including mucosal surfaces. This not only includes the effector arm of the immune system, but also regulation of immune responses in order to prevent autoimmunity. Genetic targeting of PI3K isoforms suggests that generation of PI(3,4,5)P3 by PI3K plays a critical role in promoting effector T cell responses. Consequently, the 5′- and 3′-inositol poly-phosphatases SHIP1, SHIP2, and phosphatase and tensin homolog capable of targeting PI(3,4,5)P3 are potential genetic determinants of T cell effector functions in vivo. In addition, the 5′-inositol poly-phosphatases SHIP1 and 2 can shunt PI(3,4,5)P3 to the rare but potent signaling phosphoinositide species PI(3,4)P2 and thus these SHIP1/2, and the INPP4A/B enzymes that deplete PI(3,4)P2 may have precise roles in T cell biology to amplify or inhibit effectors of PI3K signaling that are selectively recruited to and activated by PI(3,4)P2. Here we summarize recent genetic and chemical evidence that indicates the inositol poly-phosphatases have important roles in both the effector and regulatory functions of the T cell compartment. In addition, we will discuss future genetic studies that might be undertaken to further elaborate the role of these enzymes in T cell biology as well as potential pharmaceutical manipulation of these enzymes for therapeutic purposes in disease settings where T cell function is a key in vivo target.

‣ The cell as nexus: Connections between the history, philosophy and science of cell biology

O’Malley, Maureen A.; Müller-Wille, Staffan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Although the cell is commonly addressed as the unit of life, historians and philosophers have devoted relatively little attention to this concept in comparison to other fundamental concepts of biology such as the gene or species. As a partial remedy to this neglect, we introduce the cell as a major point of connection between various disciplinary approaches, epistemic strategies, technological vectors and overarching biological processes such as metabolism, growth, reproduction and evolution. We suggest that the role of the cell as a nexus forms the basis for a new philosophical and historical appreciation of cell biology. This perspective focuses less on the cell as a well-defined, stable object and places more emphasis on its role as a mediator of fundamental biological processes.

‣ Mimicking p14ARF Phosphorylation Influences Its Ability to Restrain Cell Proliferation

Vivo, Maria; Ranieri, Michela; Sansone, Federica; Santoriello, Cristina; Calogero, Raffaele A.; Calabrò, Viola; Pollice, Alessandra; La Mantia, Girolama
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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The INK4a/ARF locus on the short arm of chromosome 9 is one of the most frequently altered loci in human cancer. It is generally accepted that ARF is involved in oncogenic checkpoint pathways by sensitizing incipient cancer cells to undergo growth arrest or apoptosis through both p53-dependent and independent pathways. While intensive studies have been focused on ARF activation at the transcriptional level, only recently mechanisms governing ARF turnover have been identified. Here, we show for the first time that p14ARF is a PKC target. Prediction analysis showed many potential phosphorylation sites in PKC consensus sequences within ARF protein, and, among them, the threonine at position 8 was the most conserved. Substitution of this threonine influences both ARF stability and localization. Furthermore, a phosphomimetic ARF mutation reduces the ability to arrest cell growth although the ability to bind MDM2 and stabilize p53 result unaffected. Thus we propose that phosphorylation of ARF in both immortalized and tumor cell lines could be a mechanism to escape ARF surveillance following proliferative and oncogenic stress.; Stem Cell and Regenerative Biology

‣ Highly Upregulated Lhx2 in the Foxn1(^{−/−}) Nude Mouse Phenotype Reflects a Dysregulated and Expanded Epidermal Stem Cell Niche

Bohr, Stefan; Patel, Suraj J; Vasko, Radovan; Shen, Keyue; Huang, Guofeng; Yarmush, Martin Leon; Berthiaume, Francois
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Hair cycling is a prime example of stem cell dependent tissue regeneration and replenishment, and its regulatory mechanisms remain poorly understood. In the present study, we evaluated the effect of a blockage in terminal keratinocytic lineage differentiation in the Foxn1(^{−/−}) nude phenotype on the epithelial progeny. Most notably we found a constitutive upregulation of LIM homeobox protein 2 (Lhx2), a marker gene of epithelial stem cellness indispensible for hair cycle progression. However, histological evidence along with an erratic, acyclic rise of otherwise suppressed CyclinD1 levels along with several key markers of keratinocyte lineage differentiation indicate a frustrated expansion of epithelial stem cell niches in skin. In addition, CD49f/CD34/CD200–based profiling demonstrated highly significant shifts in subpopulations of epithelial progeny. Intriguingly this appeared to include the expansion of Oct4+ stem cells in dermal fractions of skin isolates in the Foxn1 knock-out opposed to wild type. Overall our findings indicate that the Foxn1(^{−/−}) phenotype has a strong impact on epithelial progeny and thus offers a promising model to study maintenance and regulation of stem cell niches within skin not feasible in other in vitro or in vivo models.

‣ Ovarian Cancer Spheroid Cells with Stem Cell-Like Properties Contribute to Tumor Generation, Metastasis and Chemotherapy Resistance through Hypoxia-Resistant Metabolism

Liao, Jianqun; Qian, Feng; Tchabo, Nana; Mhawech-Fauceglia, Paulette; Beck, Amy; Qian, Zikun; Wang, Xinhui; Huss, Wendy J.; Lele, Shashikant B.; Morrison, Carl D.; Odunsi, Kunle
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >105 parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. 13C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively...

‣ Glycosaminoglycan biosynthesis controls C. elegans vulval morphogenesis and is required for the first cell division during embryogenesis; Glycosaminoglycan biosynthesis controls Caenorhabditis elegans vulval morphogenesis and is required for the first cell division during embryogenesis

Hwang, Ho-Yon, 1969-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 202 leaves; 9967380 bytes; 9967186 bytes; application/pdf; application/pdf
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Morphogenesis is critical to the development of multicellular organisms. Morphogenesis is also a complex process that requires the coordination of many events, including cell division, cytoskeletal reorganization, cell-cell and cell-matrix interactions. To investigate a driving mechanism of morphogenesis in organ formation, we characterized a group of C. elegans mutants defective in vulval morphogenesis. We established that the morphogenetic defect is caused by disruption in biosynthesis of chondroitin glycosaminoglycans by molecular identification and characterization of five sqv (uashed vulva) genes. Glycosaminoglycans are known to function in development by binding a large repertoire of ligands involved in morphogenesis and wound healing, in some cases by modulating certain conserved signaling pathways, and in providing structural support in the extracellular matrix. Defects in biosynthesis of glycosaminoglycans can cause connective tissue diseases. We found that regulation of sqv-4 likely controls glycosaminoglycan biosynthesis and the aspect of vulval morphogenesis driven by chondroitin. We also characterized specific defects in separation of the plasma membrane from the eggshell and failure to initiate cytokinesis caused by mutations in sqv genes in the one-cell embryo.; by Ho-Yon Hwang.; Thesis (Ph. D.)--Massachusetts Institute of Technology...

‣ Developmental transitions of germ cell lineage of the mouse

Baltus, Andrew Edmund
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 179 leaves
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Mammalian germ cells arise during early embryogenesis and migrate to the developing gonad where, under the direction of the somatic environment, they initiate distinct sex-specific developmental programs resulting in the production of egg or sperm. Our understanding of the molecular mechanisms governing many stages of germ cell development has advanced greatly in recent years. However, many aspects of germ cell development remain entirely uncharacterized at the molecular level. In this thesis I will present projects utilizing forward and reverse genetics that generate new points of entry into poorly understood transitions during germ cell development. The X and Y chromosome do not have pairing partners during male meiosis. As a result they become silenced during this time. One mechanism that has been proposed to compensate for inactive X-linked housekeeping genes during male meiosis is X-to-autosome retropositions. We have identified a mutation within an X-to-autosome retrogene in the mouse spermatogenic mutant jsd/jsd that provides the first supporting evidence for this model.; (cont.) Evolutionary analysis indicates that since the X and Y chromosome evolved from a pair of autosomes, retroposition of this gene occurred and was maintained independently in several different mammalian lineages...

‣ Mechanisms underlying cell-to-cell diversity in clonal populations of yeast

Bumgarner, Stacie L
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 233 p.
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The FLO promoters are among the largest promoters in yeast and receive a complex combination of signals from upstream signaling pathways through their association with downstream DNA binding factors and chromatin remodelers. The genes regulated by these promoters encode cell-surface glycoproteins that mediate a range of cell-to-cell and cell-to-surface adhesions. Phenotypic diversity in clonal populations of yeast cells is mediated in part by epigenetic silencing of the FLO10 and FLO11 promoters. Silencing of the FLO promoters is heterogeneous, or variegated, within a clonal population of cells. The variegated transcription of FLO10 and FLO11 results in a population of yeast cells that exhibits cell-to-cell variability in flocculation, adhesion to and invasion of inert surfaces, and filamentous growth. In this thesis, I discuss chromatin modifying proteins that localize to the FLO10 and FLO11 promoters and act in trans to affect transcription and silencing at these promoters. I describe the results of genome-wide screens to identify additional trans-acting chromatin modifying factors that play roles in the transcriptional regulation and silencing of the FLO10 and FLO11 promoters. Some of the candidates identified in these screens had effects on FLO transcription that initially seemed paradoxical in light of contemporary theories regarding the role of chromatin structure in regulating transcription. Given that histone deacetylases generally repress transcriptional activity...

‣ Genetic analysis of programmed cell death in Drosophila melanogaster

Agapite, Julie, 1968-
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 268, [1] leaves; 28710074 bytes; 28709833 bytes; application/pdf; application/pdf
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The correct regulation of programmed cell death, or apoptosis, is critical for proper development and prevention of disease. Components of the molecular mechanisms that govern apoptosis are conserved among organisms as diverse as C. elegans, Drosophila, and mammals. A central step in the execution of cell death is the activation of caspases, a conserved family of cysteine proteases. In Drosophila, the proteins, Reaper (Rpr), Head involution defective (Hid), and Grim, induce cell death via a mechanism that involves caspase activation. In order to further elucidate the mechanisms underlying the control of apoptosis, we conducted screens for genes involved in Rpr- or Hid-induced cell death. The analysis of the mutants isolated led to several new insights. The death inducing activity of Hid is post-transcriptionally down-regulated by the Ras/MAPK pathway. This is consistent with the pro-survival activity of this pathway and is probably mediated by direct phosphorylation of Hid. Furthermore, analysis of mutations in the gene encoding the Drosophila IAP, Diapl, led to a model for how Rpr, Hid and Grim activate caspases and induce cell death. In this model, Diapl binds and inhibits caspases; Rpr, Hid, and Grim induce cell death by binding Diapl and relieving caspases of Diapl-mediated inhibition. In addition...

‣ Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival

Maia, Sara; Pelletier, Marc; Ding, Jixin; Hsu, Yen-Ming; Rao, Sambasiva P.; Cardoso, Angelo A.; Sallan, Stephen Earl; Nadler, Lee Marshall
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies. We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI. These receptors are functional as their ligation triggers activation of NF-kB, MAPK/JNK, and Akt signaling. Leukemia cells express surface BAFF and APRIL ligands, and soluble BAFF is significantly higher in leukemia patients in comparison to age-matched controls. Interestingly, leukemia cells also express surface APRIL, which seems to be encoded by APRIL-\(\delta\), a novel isoform that lacks the furin convertase domain. Importantly, we observed BM microenvironmental cells express the ligands BAFF and APRIL, including surface and secreted BAFF by BM endothelial cells. Functional studies showed that signals through BAFF-system receptors impact the survival and basal proliferation of leukemia B-cell precursors...

‣ Yogi Berra, Forrest Gump, and the discovery of Listeria actin comet tails

Portnoy, Daniel A.
Fonte: The American Society for Cell Biology Publicador: The American Society for Cell Biology
Tipo: Artigo de Revista Científica
Publicado em 01/04/2012 Português
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In 1988, eminent cell biologist Lew Tilney and newly appointed Assistant Professor of Microbiology Dan Portnoy met at a picnic and initiated a collaboration that led to a groundbreaking paper published in Journal of Cell Biology entitled “Actin filaments and the growth, movement, and spread of the intracellular bacterial parasite, Listeria monocytogenes.” The paper has been cited more than 800 times, the most of any publication in the careers of both investigators. Using an electron microscope from the Sputnik era, they assembled a stunning collection of micrographs that illustrated how L. monocytogenes enters the host cell and exploits a host system of actin-based motility to move within cells and into neighboring cells without leaving the host cell cytosol. This research captured the imagination of cell biologists and microbiologists alike and led to novel insights into cytoskeletal dynamics. Here, Portnoy provides a retrospective that shares text from the original submission that was deleted at the time of publication, along with reviewers' comments ranging from “It is really just a show and tell paper and doesn';t have any meat” to “the finding will have major impact in cell biology and in medicine. Potentially, the paper will be a classic.”

‣ Experimental and Computational Tools to Study P53 Dynamics at the Single-Cell Level

Karhohs, Kyle Wayne
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation; text Formato: application/pdf
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One of the most commonly mutated genes found in cancer is the tumor suppressor p53. p53 is a transcription factor capable of inducing cell-cycle arrest, apoptosis, senescence, and other cellular processes thought to halt the progression of a nascent cancer. As part of a stress signaling pathway, p53 is acutely activated by ionizing radiation and the formation of DNA double-strand breaks. The appearence of this DNA damage causes the concentration of p53 within the nucleus to fluctuate and pulse regularly, which can be observed in single cells using fluorescence time-lapse microscopy. From the time this was first discovered, the connection between these p53 dynamics and p53 function has been speculated upon. A key insight into this connection came from a Lahav Lab publication that demonstrated the act of pulsing, itself, controls p53-dependent transcription and cell fate. The mechanisms and molecular details behind this relationship are now an area of intense study. Another area of high interest is the broader characterization of p53 dynamics in different time-scales, genetic backgrounds, and stresses. These lines of research each depend upon single-cell measurements that are often time consuming, noisy, and yield small sample sizes. The ongoing development of experiemental and computational tools for single-cell biology is needed to overcome these limitations. In the publication referenced earlier...