The Ubiquitin–Proteasome System and Disease: Volume 4

Protein degradation, the controlled break–up of cellular proteins by intracellular proteolysis, is a major component in cellular metabolism and regulates numerous cell functions, including removal of misfolded proteins, growth and cell division, DNA repair, the immune response and the stress response to emergency conditions.
This final volume in the series focuses on malfunctions of the ubiquitin–proteasome system and their role in human disease. As such, it is the most comprehensive resource on this key topic in molecular cell biology, incorporating the unmatched expertise of the 2004 Chemistry Nobel laureates. The editors and authors comprise virtually all the top scientists in the field, including the pioneers of protein degradation research.
From the contents:Ubiquitin and cancerUbiquitin and liver cancerMuscle atrophyAggresomes and human diseaseParkin and neurodegenerationChronic neurodegenerative diseasesParkinson′s diseaseUbiquitin and virusesDruggability of the ubiquitin–proteasome system
Required reading for molecular and cell biologists, as well as physiologists with an interest in the topic.

Spis treści:
Preface.
List of Contributors.
1 Ubiquitin Signaling and Cancer Pathogenesis (Kaisa Haglund and Ivan Dikic).
1.1 Introduction.
1.2 Ubiquitin in Cancer Pathogenesis.
1.3 Targeting Ubiquitin Networks in Cancers.
1.4 Conclusions and Future Perspectives.
2 Regulation of the p53 Tumor–suppressor Protein by Ubiquitin and Ubiquitin–like Molecules (Dimitris P. Xirodimas).
2.1 Functional Domains of p53.
2.2 The Family of Ubiquitin–like Molecules.
2.3 E3 Ligases for p53.
2.4 Modification of p53 with Ubiquitin.
2.5 Requirements for Mdm2–mediated Ubiquitination of p53.
2.6 Regulation of p53 Ubiquitination.
2.7 De–ubiquitination of p53.
2.8 SUMO–1/ sentrin/smpt3.
2.9 NEDD8/Rub1.
2.10 Therapeutic Intervention through the Ubiquitin Pathway.
3 The Ubiquitinâ Proteasome System in Epstein–Barr Virus Infection and Oncogenesis (Maria G. Masucci).
3.1 Introduction.
3.2 Viral Interference with the Ubiquitinâ Proteasome System.
3.3 The EBV Life Cycle.
3.4 EBV and the Ubiquitinâ Proteasome System.
3.5 EBV–associated Malignancies.
3.6 Concluding Remarks.
4 HECT Ubiquitin–protein Ligases in Human Disease (Martin Scheffner and Olivier Staub).
4.1 Introduction.
4.2 Definition of HECT E3s.
4.3 Human HECT E3s and their Role in Disease.
4.4 E6–AP.
4.5 HECTH9.
4.6 HECT E3s with WW Domains.
4.7 Concluding Remarks.
5 Ubiquitin–independent Mechanisms of Substrate Recognition and Degradation by the Proteasome (Martin A. Hoyt and Philip Coffino).
5.1 Introduction.
5.2 Ubiquitin–independent Proteasome Substrates.
5.3 Mechanisms of Ubiquitin–independent Degradation.
5.4 Conclusion.
6 Endoplasmic Reticulum Protein Quality Control and Degradation (Antje Schäfer, Zlatka Kostova and Dieter H. Wolf).
6.1 Introduction.
6.2 ER–import, Folding and the Unfolded Protein Response.
6.3 General Principles and Components of ERQD (Endoplasmic Reticulum Quality Control and Protein Degradation).
6.4 Mechanism of ERQD.
6.5 â Overflowâ Degradation Pathways: ER–to–Golgi Transport and Autophagocytosis.
6.6 The Retrotranslocation Channel.
6.7 Metazoan ERQD.
7 Interactions between Viruses and the Ubiquitinâ Proteasome System (Jessica M. Boname and Paul J. Lehner).
7.1 Introduction.
7.2 Overview of Viruses and the Ubiquitinâ Proteasome System.
7.3 Viruses and E3 Ubiquitin–Protein Ligases.
7.4 Conclusions.
8 The Ubiquitinâ Proteasome System i n Parkinsonâ s Disease (Kevin St. P. McNaught).
8.1 Introduction.
8.2 Protein Handling in the CNS.
8.3 The UPS and Protein Mishandling in PD.
8.4 Parkin.
8.5 UCH–L1.
8.6 α–Synuclein.
8.7 Dardarin/LRRK2.
8.8 PINK1.
8.9 DJ–1.
8.10 Proteasomal Dysfunction in Sporadic PD.
8.11 Conclusion.
9 The Molecular Pathway to Neurodegeneration in Parkin–Related Parkinsonism (Ryosuke Takahashi).
9.1 Introduction.
9.2 Parkin is an E3 Ubiquitin Ligase.
9.3 Substrates of Parkin.
9.4 The Animal Models of AR–JP.
9.5 Future Directions.
10 Parkin and Neurodegeneration (Sathya R. Sriram, Valina L. Dawson and Ted M. Dawson).
10.1 Introduction.
10.2 AR JP and Parkin.
10.3 Parkin in the Ubiquitinâ Proteasome Pathway.
10.4 Parkin in Neuroprotection.
10.5 Parkin and Other PD–linked Genes.
10.6 Mechanisms of Parkin Dysfunction.
10.7 Animal Models of Parkin Deficiency.
10.8 Concluding Remarks.
Index.

Nota biograficzna:
R. John Mayer, School of Biomedical Sciences, University of Nottingham Medical School, Queenâ s Medical Centre, Nottingham has studied Mechanisms of intracellular proteolysis for 35 years. He was made a Fellow of the Royal College of Pathologists for the discovery by ubiquitin immunocytochemistry of cortical Lewy bodies and characterizing the molecular neuropathology of dementia with Lewy bodies (DLB). DLB is the second commonest cause of cognitive decline in the elderly of Alzheimerâ s disease. Prof. Mayer also discovered ubiquitylated proteins in aggregates (inclusions) in neurones in the brain in all the chronic neurodegenerative diseases. Prof. Mayer is now using sophisticated genetic methods in transgenic mice to manipulate the ubiquitin proteasome system in the brain in order to model the chronic neurodegenerative diseases. Prof. Mayer also has a st rong collaborative research programme with colleagues in the University of Kyoto on gankyrin which is the first liver oncoprotein and a subunit of the 26S proteasome which controls the ubiquitylation of proteins including p53.
Aaron Ciechanover is a Distinguished Professor in the Cancer and Vascular Biology Research Center of the Technion Institute in Haifa, Israel. He received his M.Sc. (1971) and M.D. (1975) from â Hadassahâ and the Habrew University in Jerusalem, and his D.Sc. (1982) from the Faculty of Medicine of the Technion. There, he and Avram Hershko discovered that covalent attachment of ubiquitin to the target substrate signals it for degradation. They also discovered the three enzymes that catalyze conjugation, elucidated action and recycling. As a postdoc with Harvey Lodish at MIT (Cambridge, MA, USA), he together with Alexander Varshavsky and Daniel Finley, demonstrated that the ubiquitin system is involved in targeting normal short–lived proteins in cells. In 2004, he received the Nobel Prize for chemistry, jointly with Avram Hershko and Irwin Rose.
Martin Rechsteiner is Professor of Biochemistry at the University of Utah. Intracellular proteolysis has been his principal scientific interest over the past twenty–five years. During that time his laboratory discovered and functionally characterized the 26S proteasome as well as several proteasome as well as several proteasome activators. They also proposed that PEST sequences, regions of the polypeptide sequence rich in proline (P), glutamic acid (E), serine (S), and threonine (T), target proteins for rapid degradation.

Okładka tylna:
Protein degradation, the controlled break–up of cellular proteins by intracellular proteolysis, is a major component in cellular metabolism and regulates numerous cell functions, including removal of misfolded proteins, growth and cell division, DNA repair, the immune response and the stress respo nse to emergency conditions.
This final volume in the series focuses on malfunctions of the ubiquitin–proteasome system and their role in human disease. As such, it is the most comprehensive resource on this key topic in molecular cell biology, incorporating the unmatched expertise of the 2004 Chemistry Nobel laureates. The editors and authors comprise virtually all the top scientists in the field, including the pioneers of protein degradation research.
From the contents:Ubiquitin and cancerUbiquitin and liver cancerMuscle atrophyAggresomes and human diseaseParkin and neurodegenerationChronic neurodegenerative diseasesParkinson′s diseaseUbiquitin and virusesDruggability of the ubiquitin–proteasome system
Required reading for molecular and cell biologists, as well as physiologists with an interest in the topic.