381 research outputs found
Cancer Immunotherapy: The Dawn of Antibody Cocktails
No full textSince the approval of the first monoclonal antibody (mAb), rituximab, for hematological malignancies, almost 30 additional mAbs have been approved in oncology. Despite remarkable advances, relatively weak responses and resistance to antibody monotherapy remain major open issue. Overcoming resistance might require combinations of drugs blocking both the major target and the emerging secondary target. We review clinically approved combinations of antibodies and either cytotoxic regimens (chemotherapy and irradiation) or kinase inhibitors. Thereafter, we focus on the most promising and currently very active arena that combines mAbs inhibiting immune checkpoints or growth factor receptors. Clinically approved and experimental oligoclonal mixtures of mAbs targeting different antigens (hetero-combinations) or different epitopes of the same antigen (homo-combinations) are described. Effective oligoclonal mixtures of antibodies that mimic the polyclonal immune response will likely become a mainstay of cancer therapy
Molecular mechanism of ubiquitin-dependent traffic
No full textPosttranslational modification (PTM) of signaling receptors by the covalent attachment of one, or often more, ubiquitin (Ub) moieties has emerged as the major regulatory mechanism responsible for receptor “downregulation.” Pioneering work in yeast has demonstrated that Ub is required for the first step in cargo internalization as well as for targeting cargos to vacuoles (the yeast equivalent of lysosomes) [1, 2]. Following these initial observations, there are now numerous reports of ubiquitination of a vast array of mammalian signaling receptors, such as RTKs, GPCRs, MHC-I, NOTCH, various channels and transporters, cytokine, and interferon receptors (reviewed in [3–8]). The molecular basis of Ub-dependent regulation of receptor endocytosis is being clarified. In this chapter, we will give a general overview of the mammalian system
EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance
No full textThe epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms
Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases
No full textWhen appended to the epidermal growth factor receptor ( EGFR), ubiquitin serves as a sorting signal for lysosomal degradation. Here we demonstrate that the ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8. EGF stimulates receptor neddylation, which enhances subsequent ubiquitylation, as well as sorting of EGFR for degradation. Multiple lysine residues, located within the tyrosine kinase domain of EGFR, serve as attachment sites for Nedd8. A set of clathrin coat-associated binders of ubiquitin also bind Nedd8, but they undergo ubiquitylation, not neddylation. We discuss the emerging versatility of the concerted action of ubiquitylation and neddylation in the process that desensitizes growth factor-activated receptor tyrosine kinases
Endocytosis in the Spatial Control of Polarised Cell Functions
No full textEndocytosis, originally thought of as a device to transport nutrients and membrane-associated molecules across the plasma membrane through vesicles, is emerging as a connectivity infrastructure (which we have called the endocytic matrix) of different cellular networks necessary for the execution of various cellular programmes. A primary role of the endocytic matrix is the delivery of space- and time-resolved signals to the cell, and it is thus essential for the execution of polarised functions. Here, by discussing paradigmatic cases, we intend to outline emerging concepts of how the endocytic wiring system functions as a highly interconnected intracellular highway that mobilises membrane and signalling molecules, ensuring polarised compartmentalisation of signals. We will specifically focus on two exemplar cases: the impact of the endocytic matrix on cell migration and on asymmetric cell division. In each of these cases, endocytosis and recycling have been shown to ensure the asymmetric distribution of biological molecules, which, in turn, is crucial for proper polarised cellular function
Kristian Lundbergs gudomliga komedi : En intertextuell analys av Yarden, Mörkret skulle vara som ljuset och Och allt skall vara kärlek
No full textThis essay explores the intertextual qualities in and between Kristian Lundberg’s works Yarden, Mörkret skulle vara som ljuset and Och allt skall vara kärlek. Read as a trilogy, it bears a thematic resemblance to Dante Alighieri’s Divine Comedy; an autofictional depiction of emancipation from alienation by grace. To reach this conclusion, I use Julia Kristeva’s theory of intertextuality and Roland Barthes’ post-structuralist differention of Work and Text together with his notion of the Paper-Author. Through a kaleidoscopic reading of the two trilogies, Dante and Kristian become pilgrims in the word’s true, etymological sense: foreigners, both religious and materialistic. As such, they walk the spiritual and material world making no distinction between the two towards a love whose essential nature is twofold: at once human and divine
Functional and computational analysis of RNA-binding proteins and their roles in cancer
No full textThesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2014.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 197-200).This work is concerned with mRNA processing in mammalian cells and proceeds in two parts. In the first part, I introduce a computational framework for inferring the abundances of mRNA isoforms using high-throughput RNA sequencing data. This framework was applied to study the targets of the ubiquitous splicing factor hnRNP H in human cells. In the second part, I describe an experimental study of the Musashi (hnRNP-like) family of RNA-binding proteins in stem cells and cancer cells, which incorporates computational analyses that rely heavily on the framework developed in part one. In sum, this work provides a computational framework of general use in global analyses of RNA processing and its protein regulators, as well as functional insights into a family of poorly understood RNA-binding proteins. Several related analyses and techniques developed as part of the thesis are described in Appendix A-C. Appendix A describes a study of activity-dependent gene expression and mRNA processing in the mouse olfactory bulb. It uses computational techniques developed in part one of the thesis. Appendix B describes a technique for quantitative visualization of alternative splicing from RNA sequencing data and its integration into a genome browser. Appendix C describes a method for clonal analysis of neural stem cell growth and differentiation in culture using live imaging and `microdot' plates, developed as part of the work presented in part one of the thesis.by Yarden Katz.Ph. D
Two NDR kinase-MOB complexes function as distinct modules during septum formation and tip extension in Neurospora crassa
No full textP>NDR kinases are important for growth and differentiation and require interaction with MOB proteins for activity and function. We characterized the NDR kinases and MOB activators in Neurospora crassa and identified two NDR kinases (COT1 and DBF2) and four MOB proteins (MOB1, MOB2A, MOB2B and MOB3/phocein) that form two functional NDR-MOB protein complexes. The MOB1-DBF2 complex is not only essential for septum formation in vegetative cells and during conidiation, but also functions during sexual fruiting body development and ascosporogenesis. The two MOB2-type proteins interact with both COT1 isoforms and control polar tip extension and branching by regulating COT1 activity. The conserved region directly preceding the kinase domain of COT1 is sufficient for the formation of COT1-MOB2 heterodimers, but also for kinase homodimerization. An additional N-terminal extension that is poorly conserved, but present in most fungal NDR kinases, is required for further stabilization of both types of interactions and for stimulating COT1 activity. COT1 lacking this region is degraded in a mob-2 background. We propose a specific role of MOB3/phocein during vegetative cell fusion, fruiting body development and ascosporogenesis that is unrelated to the three other MOB proteins and NDR kinase signalling
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