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Proteasome activator enhances survival of Huntington's disease neuronal model cells
February 28, 2007To function, each living cell needs both to build new and to degrade old or damaged proteins. To accomplish that, a number of intracellular systems work in concert to keep the cell healthy and from clogging up with damaged proteins. When proteins or peptides mutate, they can present major problems to the clearing up of the intracellular environment. In Huntington's disease (HD) the disease provoking mutation in the huntingtin gene eventually causes the cell to build up intranuclear and cellular inclusions of protein-aggregates, made up primarily of huntingtin. One cellular organelle with a central role of clearing such protein build up in the cell is the ubiquitin proteasome system (UPS).
In Huntington's disease (HD) brains and other tissues, UPS activity is inhibited and intraneuronal nuclear protein aggregates of mutant huntingtin in HD brains indicate dysfunction of the UPS. From these results, we hypothesized that enhancing UPS function would improve catalytic degradation of abnormal proteins in HD. We first genetically engineered proteasome activators involved in either non-ubiquitinated protein degradation pathways (PA28Æ'×) or subunits of PA700, the 26S proteasome ubiquitinated pathway (S5a) into transducible lentiviral vectors. To address the therapeutic hypothesis experimentally, we transduced UPS subunits into HD skin fibroblasts or HD mutant protein expressing striatum-derived neurons. We determined how this intervention altered cell survival after exposure to toxins known to simulate pathological mechanisms in HD.
The manuscript shows that cellular changes due to expression of huntingtin protein with longer CAG repeats can reduce the ubiquitin proteasome system (UPS) function in Huntington¡¦s disease cells. Following compromise of the UPS, the overexpression of proteasome activator PA28 can specifically recover proteasome function and improve cell viability in both HD model and patient cells.
These remarkable results demonstrate for the first time that it is possible to intervene therapeutically in the proteolytic pathways and organelles that participate in the specific degradation of misfolded and abnormal proteins.
Public Library of Science
These remarkable results demonstrate for the first time that it is possible to intervene therapeutically in the proteolytic pathways and organelles that participate in the specific degradation of misfolded and abnormal proteins.
Public Library of Science
Proteasome Current Events and Proteasome News RSSApproved lymphoma drug shows promise in early tests against bone cancer
A drug already approved for the treatment of lymphoma may also slow the growth of the most deadly bone cancer in children and teens, according to an early-stage study published online today in the International Journal of Cancer.
KEAP1 Keeps major cancer-promoting protein at bay
A tumor-suppressing protein snatches up an important cancer-promoting enzyme and tags it with molecules that condemn it to destruction, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports this week in the journal Molecular Cell.
Weill Cornell Researchers Discover New Anti-Tuberculosis (TB) Compounds
Attempts to eradicate tuberculosis (TB) are stymied by the fact that the disease-causing bacteria have a sophisticated mechanism for surviving dormant in infected cells.
Study reveals how a common virus eludes the immune system
Viruses have numerous tricks for dodging the immune system. In the September 7, 2009 issue of the Journal of Cell Biology, Stagg et al. reveal a key detail in one of these stratagems, identifying a protein that enables cyto¬megalovirus to shut down an antiviral defense (online August 31).
Researchers identify new, cancer-causing role for protein
The mainstay immune system protein TRAF6 plays an unexpected, key role activating a cell signaling molecule that in mutant form is associated with cancer growth, researchers at The University of Texas M. D. Anderson Cancer Center report in the Aug. 28 edition of Science.
Fine-tuning an anti-cancer drug
Cancer remains a deadly threat despite the best efforts of science. New hopes were raised a few years ago with the discovery that the uncontrolled growth of cancer cells could be thwarted by blocking the action of proteasomes.
Protein plays unexpected role protecting chromosome tips
A protein specialist that opens the genomic door for DNA repair and gene expression also turns out to be a multi-tasking workhorse that protects the tips of chromosomes and dabbles in a protein-destruction complex, a team lead by researchers at The University of Texas M. D. Anderson Cancer Center reports in the Aug. 13 edition of Molecular Cell.
Unraveling how cells respond to low oxygen
Gary Chiang, Ph.D., and colleagues at Burnham Institute for Medical Research (Burnham) have elucidated how the stability of the REDD1 protein is regulated.
Researchers pinpoint a new enemy for tumor-suppressor p53
Researchers at The University of Texas M. D. Anderson Cancer Center have identified a protein that marks the tumor suppressor p53 for destruction, providing a potential new avenue for restoring p53 in cancer cells.
Self-digestion as a means of survival
In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process - known as autophagy - takes place in special organelles called autophagosomes.
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The Proteasome in Neurodegeneration by Leonidas Stefanis (Editor), J.N. Keller (Editor) There is increasing evidence that links together various common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. Finding common themes in the pathophysiology of such disorders is increasingly important. This text addresses such a common theme—the proteasome. Since the discovery of the proteasome some 20 years ago, significant strides have been made in our understanding of proteasome biology and our understanding of the role the proteasome plays in a wide variety of biochemical events. Taken together, these studies have confirmed an important role for the proteasome in the fields of cell biology, oncology, immunology, gerontology, and neuroscience. The focus of this book is to provide an in depth analysis and provocative discussion of what... |
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Protein Degradation: The Ubiquitin-Proteasome System and Disease by R. John Mayer (Editor), Aaron J. Ciechanover (Editor), Martin Rechsteiner (Editor) This final volume in the series focuses on malfunctions of the ubiquitin-proteasome system and their role in human disease. The editors and authors represent unmatched expertise, comprising virtually all the top scientists in the field, including the pioneers of protein degradation research. From the contents: Ubiquitin and cancer Ubiquitin and liver cancer Muscle atrophy Aggresomes and human disease Parkin and neurodegeneration Chronic neurodegenerative diseases Parkinson's disease Ubiquitin and viruses Druggability of the ubiquitin-proteasome system Required reading for molecular and cell biologists, as well as physiologists with an interest in the... |
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Proteasomes : The World of Regulatory Proteolysis (Molecular Biology Intelligence Unit) by Wolfgang Hilt (Editor), Dieter H. Wolf (Editor) This book highlights proteasome structures and how they are related to different aspects of proteasome function. Moreover, the book reports on the functional roles these highly developed proteolytic machines play within the cell. It was a great surprise to the scientific world that proteolysis provides crucial functions in cellular regulation. The surprise was even greater when it was found that not lysosomes, but protease complexes with remarkably sophisticated architectures were responsible for the control of essential regulatory events. Excitingly, proteasomes were found to be involved in widespread functions of cell physiology, which included degradation of protein waste, antigen presentation, regulation of cell metabolism and cell differentiation as well as control of the... |
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Protein Degradation: The Ubiquitin-Proteasome System by R. John Mayer (Editor), Aaron J. Ciechanover (Editor), Martin Rechsteiner (Editor) The second volume in a new series dedicated to protein degradation, this book discusses the mechanism and cellular functions of targeted protein breakdown via the ubiquitin pathway. Drawing on the combined knowledge of the world's leading protein degradation experts, this handy reference compiles information on the proteasome-mediated degradation steps of the ubiquitin pathway. In addition to proteasomal function and regulation, it also presents the latest results on novel members of the ubiquitin superfamily and their role in cellular regulation. Further volumes in the series cover the function of ubiquitin-protein ligases, and the roles of the ubiquitin pathway in regulating key cellular processes, as well as its pathophysiological disease states. |
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Proteasomes/Multicatalytic Proteinase Complexes: Enzyme and Protein (Enzyme & Protein) by S. Wilk (Editor) Proteasomes (multicatalytic proteinase complexes) are high molecular mass proteolytic molecules found in relatively high concentrations in all eukaryotic cells. Evidence for their essential role in several fundamental cellular processes coupled with their unique structural and catalytic properties accounts for the explosive growth of research on these molecules. They participate in extralysosomal protein metabolism, in the degradation of ubiquitinylated proteins such as cyclins, oncoproteins and transcription factors and in the generation of antigens from endogenous proteins in the MHC-1 pathway. Bringing together almost all of the major contributors to this rapidly evolving research area, this publication is the first to offer a ready source of information on the structure, properties... | |
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The Ubiquitin-proteasome System (Essays in Biochemistry) by J. Mayer (Author), R. Layfield (Author) The importance of the ubiquitin-proteasome system in cellular homoeostasis was emphasized by the award of the 2004 Nobel Prize in Chemistry to the discoverers of ubiquitin as a cofactor for intracellular non-lysosomal proteolysis. There is a voluminous literature showing that protein ubiquitylation and the degradation of ubiquitylated proteins by the 26 S proteasome controls almost every regulatory process in the cell. The contributors to this volume of "Essays in Biochemistry" focus on many different aspects of the role of the ubiquitin system in intracellular proteolysis, not only in cellular homoeostasis, but also in relation to disease. Ubiquitylation compliments and rivals protein phosphorylation/dephosphorylation in the regulation of cellular activities. Understanding the... | |
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The Ubiquitin Proteasome System in the Central Nervous System: From Physiology to Pathology by Mario Di Napoli (Editor), Cezary Wojcik (Editor) The book focuses on the role of ubiquitin proteasome system (UPS) in central nervous system. Proteasomes are large multicatalytic proteinase complexes that are found in the cytosol and in the nucleus of eukaryotic cells with a central role in cellular protein turnover. The UPS has a central role in the selective degradation of intracellular proteins. In addition to serving as a means to rapidly eliminate short-lived regulatory proteins involved in cell cycle, cell growth, and differentiation, in periods of stress rapid elimination of denatured, misfolded and damaged proteins by the proteasome becomes a critical determinant of cell fate. These aspects are analysed in central nervous system physiology and pathology. |
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The Proteasome-Ubiquitin Protein Degradation Pathway by Peter Zwickl (Editor), Wolfgang Baumeister (Editor) This volume gives a complete overview of the structure and function of the proteasome, its regulators and inhibitors, and its cellular importance, in conjunction with the ubiquitin system, for the degradation of regulatory proteins and the generation of immunogenic peptides. |
![Nucleotide excision repair and the ubiquitin proteasome pathway-Do all roads lead to Rome? [An article from: DNA Repair]](http://ecx.images-amazon.com/images/I/51FZ3K9Y7XL._SL160_.jpg) |
Nucleotide excision repair and the ubiquitin proteasome pathway-Do all roads lead to Rome? [An article from: DNA Repair] by S.H. Reed (Author), T.G. Gillette (Author) This digital document is a journal article from DNA Repair, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: It is clear that components of the proteasome and the ubiquitin proteasome pathway play a direct mechanistic role in the regulation of a variety of DNA repair processes. Intriguingly, a wealth of evidence suggests that this is also the case during the regulation of gene transcription. Here we review our current understanding of how the ubiquitin proteasome pathway influences nucleotide excision repair, and discuss how studies that investigate the role of this pathway in the regulation of gene transcription might also... |
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Competitor Analysis: Proteasome Inhibitors by La Merie S.L. (Author) The Competitive Intelligence Report Proteasome Inhibitors updated as of June 2008 provides a competitor analysis in the development pipeline of novel small molecules and peptides targeting the proteasome for treatment of cancer, especially of multiple myeloma. The report also provides information about the market size of established proteasome inhibitor therapy. Among the companies active in the field of proteasome inhibitors are Millennium Pharmaceuticals and Johnson & Johnson and many others. The report includes a compilation of current active projects in research and development of Hsp90 Inhibitors. Competitor projects are listed in a tabular format providing Information on: Drug Codes, Target / Mechanism of Action, Class of Compound, Company, Product category, ... |
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