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Author: Qizhi Sun Publisher: ISBN: Category : Languages : en Pages :
Book Description
Ubiquitination plays a fundamental role in determining protein fate. Once ubiquitinated, the cargo is directed to the proteasome for partial or complete degradation or lysosome for complete degradation. Failing to eliminate these cargos results in the accumulation of toxic proteins that contribute to neurodegenerative and immunological diseases, cancer and other human maladies. Thus, identifying proteins subject to ubiquitin-mediated degradation and characterizing the mechanisms governing these processes underscores their importance to human health. The calcium/calmodulin-dependent serine protein kinase (CASK) is one such protein that is required for brain development. However, mutations that cause CASK to accumulate are correlated to X-linked mental retardation and autism spectrum disorder in humans. I have investigated CASK protein turnover and found that the protein is constantly degraded. This degradation, however, is only partial suggesting that the peptides generated have functions distinct from the full-length polypeptide. Subsequent analyses revealed that these peptides form as a result of CASK being first phosphorylated and then ubiquitinated prior to its limited degradation in the proteasome. During these investigations I identified poly ADP-ribosyl transferase-like 2 (PARP-2) as a protein also degraded through the ubiquitin-proteasome system. PARP-2 degradation occurs when cells are grown in the presence of serum and Ro52 was identified as a candidate E3 ubiquitin ligase required for ubiquitination. Interestingly, when cells are serum-starved, PARP-2 was sequestered to an SDS-insoluble fraction by a yet-to-be identified mechanism. Finally, further investigations with Ro52 revealed that when ectopically expressed, cells develop large circular structures, which I identified to be autophagosomes, the intermediate organelles in autophagy that selectively target ubiquitinated cargo for lysosomal degradation. The RING finger domain of Ro52 and its E3 ligase activity are, however, not required for this process and the deletion of the RING domain does not affect the inclusion and targeting of ubiquitinated proteins to the autophagosomes. Together, these results from studying two disparate proteins, CASK and PARP-2, not only highlight the selective ability of ubiquitination to specify the limited or complete degradation of proteins, but also shed new light on Ro52 as an adaptor involved in the autophagic turnover of proteins in the lysosome.
Author: Qizhi Sun Publisher: ISBN: Category : Languages : en Pages :
Book Description
Ubiquitination plays a fundamental role in determining protein fate. Once ubiquitinated, the cargo is directed to the proteasome for partial or complete degradation or lysosome for complete degradation. Failing to eliminate these cargos results in the accumulation of toxic proteins that contribute to neurodegenerative and immunological diseases, cancer and other human maladies. Thus, identifying proteins subject to ubiquitin-mediated degradation and characterizing the mechanisms governing these processes underscores their importance to human health. The calcium/calmodulin-dependent serine protein kinase (CASK) is one such protein that is required for brain development. However, mutations that cause CASK to accumulate are correlated to X-linked mental retardation and autism spectrum disorder in humans. I have investigated CASK protein turnover and found that the protein is constantly degraded. This degradation, however, is only partial suggesting that the peptides generated have functions distinct from the full-length polypeptide. Subsequent analyses revealed that these peptides form as a result of CASK being first phosphorylated and then ubiquitinated prior to its limited degradation in the proteasome. During these investigations I identified poly ADP-ribosyl transferase-like 2 (PARP-2) as a protein also degraded through the ubiquitin-proteasome system. PARP-2 degradation occurs when cells are grown in the presence of serum and Ro52 was identified as a candidate E3 ubiquitin ligase required for ubiquitination. Interestingly, when cells are serum-starved, PARP-2 was sequestered to an SDS-insoluble fraction by a yet-to-be identified mechanism. Finally, further investigations with Ro52 revealed that when ectopically expressed, cells develop large circular structures, which I identified to be autophagosomes, the intermediate organelles in autophagy that selectively target ubiquitinated cargo for lysosomal degradation. The RING finger domain of Ro52 and its E3 ligase activity are, however, not required for this process and the deletion of the RING domain does not affect the inclusion and targeting of ubiquitinated proteins to the autophagosomes. Together, these results from studying two disparate proteins, CASK and PARP-2, not only highlight the selective ability of ubiquitination to specify the limited or complete degradation of proteins, but also shed new light on Ro52 as an adaptor involved in the autophagic turnover of proteins in the lysosome.
Author: A.J. Rivett Publisher: Elsevier Science ISBN: 9780762303878 Category : Science Languages : en Pages : 0
Book Description
This volume brings together a set of reviews that provide a summary of our current knowledge of the proteolytic machinery and of the pathways of protein breakdown of prokaryotic and eukaryotic cells. Intracellular protein degradation is much more than just a mechanism for the removal of incorrectly folded or damaged proteins. Since many short-lived proteins have important regulatory functions, proteolysis makes a significant contribution to many cellular processes including cell cycle regulation and transciptional control. In addition, limited proteolytic cleavage can provide a rapid and efficient mechanism of enzyme activation or inactivation in eukaryotic cells. In the first chapter, Maurizi provides an introduction to intracellular protein degradation, describes the structure and functions of bacterial ATP-dependent proteases, and explores the relationship between chaperone functions and protein degradation. Many of the principles also apply to eukaryotic cells, although the proteases involved are often not the same. Interestingly, homologues of one of the bacterial proteases, Ion protease, have been found in mitochondria in yeast and mammals, and homologues of proteasomes, which are found in all eukaryotic cells (see below), have been discovered in some eubacteria. Studies of proteolysis in yeast have contributed greatly to the elucidation of both lysosomal (vacuolar) and nonlysosomal proteolytic pathways in eukaryotic cells. Thumm and Wolf (chapter 2) describe studies that have elucidated the functions of proteasomes in nonlysosomal proteolysis and the contributions of lysosomal proteases to intracellular protein breakdown. Proteins can be selected for degradation by a variety of differen mechanisms. The ubiquitin system is one complex and highly regulated mechanism by which eukaryotic proteins are targetted for degradation by proteosomes. In chapter 3, Wilkinson reviews the components and functions of the ubiquitin system and considers some of the known substrates for this pathway which include cell cycle and transcriptional regulators. The structure and functions of proteosomes and their regulatory components are described in the two subsequent chapters by Tanaka and Tanahashi and by Dubiel and Rechsteiner. Proteasomes were the first known example of threonine proteases. They are multisubunit complexes that, in addition to being responsible for the turnover of most short-lived nuclear and cytoplasmic protein, are also involved in antigen processing for presentation by the MHC class I pathway. Recent studies reviewed by McCracken and colleagues (chapter 6) lead to the exciting conclusion that some ER-associated proteins are degraded by cytosolic proteasomes. Lysosomes are responsible for the degradation of long-lived proteins and for the enhanced protein degradation observed under starvation conditions. In chapter 7 Knecht and colleagues review the lysosomal proteases and describe studies of the roles of lysosomes and the mechanisms for protein uptake into lysosomes. Methods of measuring the relative contribution of different proteolytic systems (e.g., ubiquitin-proteasome pathway, calcium-dependent proteases, lysosomes) to muscle protein degradation, and the conclusions from such studies, are reviewed by Attai and Taillinder in the following chapter. Finally, proteases play an important role in signaling apoptosis by catalyzing the limited cleavage of enzymes. Mason and Beyette review the role of the major players, caspases, which are both activated by and catalyze limite proteolysis, and also consider the involvement of other protoelytic enzymes in this pathway leading cell death.
Author: Irwin M. Arias Publisher: John Wiley & Sons ISBN: 1119436826 Category : Medical Languages : en Pages : 1156
Book Description
Bridging the gap between basic scientific advances and the understanding of liver disease — the extensively revised new edition of the premier text in the field. The latest edition of The Liver: Biology and Pathobiology remains a definitive volume in the field of hepatology, relating advances in biomedical sciences and engineering to understanding of liver structure, function, and disease pathology and treatment. Contributions from leading researchers examine the cell biology of the liver, the pathobiology of liver disease, the liver’s growth, regeneration, metabolic functions, and more. Now in its sixth edition, this classic text has been exhaustively revised to reflect new discoveries in biology and their influence on diagnosing, managing, and preventing liver disease. Seventy new chapters — including substantial original sections on liver cancer and groundbreaking advances that will have significant impact on hepatology — provide comprehensive, fully up-to-date coverage of both the current state and future direction of hepatology. Topics include liver RNA structure and function, gene editing, single-cell and single-molecule genomic analyses, the molecular biology of hepatitis, drug interactions and engineered drug design, and liver disease mechanisms and therapies. Edited by globally-recognized experts in the field, this authoritative volume: Relates molecular physiology to understanding disease pathology and treatment Links the science and pathology of the liver to practical clinical applications Features 16 new “Horizons” chapters that explore new and emerging science and technology Includes plentiful full-color illustrations and figures The Liver: Biology and Pathobiology, Sixth Edition is an indispensable resource for practicing and trainee hepatologists, gastroenterologists, hepatobiliary and liver transplant surgeons, and researchers and scientists in areas including hepatology, cell and molecular biology, virology, and drug metabolism.
Author: Aaron J. Ciechanover Publisher: Wiley-Liss ISBN: Category : Medical Languages : en Pages : 256
Book Description
The field of cellular proteolysis is advancing rapidly and has great potential impact in a variety of research and clinical areas, including AIDS and cancer research and treatment. The editors, pioneers in the field of cellular and protein research, describe our current understanding of the three major cellular proteolytic systems: the ubiquitin system, the lysosomal and vacuolar systems, and physiological and pathophysiological cellular proteolysis.
Author: Rosa Barrio Publisher: Springer Nature ISBN: 3030382664 Category : Science Languages : en Pages : 350
Book Description
This book, written by members of the European network PROTEOSTASIS, provides an up-to-date review of the research regarding protein homeostasis in health and disease. With new discoveries contributing to the increasing complexity of this topic, the book offers a detailed overview of the pathways regulating protein homeostasis, including autophagy and the ubiquitin protein family. Following a basic introduction, it explains how defects in protein homeostasis contribute to numerous pathologies, including cancer, neurodegeneration, inflammation and a number of rare diseases. In addition, it discusses, the role of protein homeostasis in cellular development and physiology. Highlighting the latest research in the field of protein homeostasis and its implications for various clinically relevant diseases, the book appeals to researchers and clinicians, while also offering a reference guide for scholars who are new to the field.
Author: Leonidas Stefanis Publisher: Springer Science & Business Media ISBN: 0387285008 Category : Medical Languages : en Pages : 314
Book Description
In the last 50 years a wealth of information has allowed us to understand the contribution of various regulatory factors that alter mRNA and protein s- thesis to a variety of physiological and pathological conditions. However, such regulation is only one of many factors that contribute to the levels of a given p- tein. One major factor that has been relatively obscure until recently has been the contribution of protein degradation to the regulation of the steady state level of protein expression and protein function. This rapidly evolving field has made a significant mark on the scientific community, as highlighted by the Award of the Nobel Prize in Chemistry for 2004 to Aaron Ciechanover, Avram Hershko and Irwin Rose for their pioneering work on the ubiquitin-proteasome system (UPS) of protein degradation, which is the subject of this volume. In recent years e- dence has been accumulating that suggests a role for UPS function in both ph- iological and pathological settings. In particular, studies have implicated a central role for the UPS in cell cycle regulation, cancer and neurodegeneration. Two points are however worth bearing in mind: First, ubiquitin’s function appears to extend far beyond the UPS and protein degradation; second, there are other important systems of intracellular protein degradation, most notably autophagic systems through the lysosomes, and these may also be involved in disease pat- physiology.
Author: Julian Adams Publisher: Springer Science & Business Media ISBN: 1592597947 Category : Medical Languages : en Pages : 319
Book Description
A panel of leading academic and pharmaceutical investigators takes stock of the remarkable work that has been accomplished to date with proteasome inhibitors in cancer, and examines emerging therapeutic possibilities. The topics range from a discussion of the chemistry and cell biology of the proteasome and the rationale for proteasome inhibitors in cancer to a review of current clinical trials underway. The discussion of rationales for testing proteasome inhibitors in cancer models covers the role of the proteasome in NF-kB activation, the combining of conventional chemotherapy and radiation with proteasome inhibition, notably PS-341, new proteasome methods of inhibiting viral maturation, and the role of protesome inhibition in the treatment of AIDS. The authors also document the development of bortezomib (VelcadeTM) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma.
Author: Pooja Dhiman Publisher: BoD – Books on Demand ISBN: 9535135074 Category : Science Languages : en Pages : 176
Book Description
This book covers current advances in disorders associated with lysosomal function along with techniques to study its function. All chapters are complete in themselves but united under a common research study topic. This publication aims at providing a thorough overview of the latest research efforts by international authors on lysosomal diseases and opens new possible research paths.
Author: Aldrin V. Gomes Publisher: ISBN: 9781536135190 Category : Science Languages : en Pages : 287
Book Description
Over the last decade, major advancements in our understanding of the ubiquitin-proteasome system (UPS) have occurred. This book focuses on recent trends in the UPS. The UPS is possibly the most complex of all intracellular pathways - as close to 7% of all genes in the human genome make up part of the UPS. This complex system serves as an essential role in intracellular protein degradation, and because of its critical function, improper functioning of the UPS is associated with nearly all know diseases, including cancer, cardiovascular disease, and neurological diseases. The proteolytic component of the UPS is the proteasome, a multicatalytic complex found in the nucleus and cytoplasm. Another form of the proteasome, the immunoproteasome, is less abundant than the constitutive proteasome, but is important in immune response and degradation of oxidized proteins, and recent research suggests that it may be important in longevity. The articles in this book discuss recent findings which indicate that mutations in proteins involved with the UPS are associated with genetic diseases such as familial dilated cardiomyopathy, Nakajo syndrome, and spinal muscular atrophy (X-linked). Some chapters also discuss recent results which suggest that the UPS is heavily regulated by post-translational modifications such as phosphorylation, acetylation, and methylation. The UPS is also heavily regulated by ubiquitination itself. This book contains a research article using PubMed bibliometric data to present current research trends in the UPS. Articles are written so that no one tissue is emphasized to allow readers from any discipline to benefit from this information.
Author: Qizhi Sun
Author: Qizhi Sun
Author: Milton J. Schlesinger
Author: A.J. Rivett
Author: Irwin M. Arias
Author: Aaron J. Ciechanover
Author: Rosa Barrio
Author: Leonidas Stefanis
Author: Julian Adams
Author: Pooja Dhiman
Author: Aldrin V. Gomes