Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets

被引:457
作者
Bedford, Lynn [2 ]
Lowe, James
Dick, Lawrence R. [1 ]
Mayer, R. John [2 ]
Brownell, James E. [1 ]
机构
[1] Millennium Pharmaceut Inc, Cambridge, MA 02139 USA
[2] Univ Nottingham, Sch Biomed Sci, Nottingham NG7 2UH, England
关键词
KAPPA-B ACTIVATION; VHL TUMOR-SUPPRESSOR; CULLIN-RING LIGASES; X-LINKED INHIBITOR; MYCOBACTERIUM-TUBERCULOSIS; NEDD8-ACTIVATING ENZYME; MULTIPLE-MYELOMA; LYS63-LINKED POLYUBIQUITIN; NEURODEGENERATIVE DISEASE; DEUBIQUITINATING ENZYME;
D O I
10.1038/nrd3321
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The ubiquitin-proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.
引用
收藏
页码:29 / 46
页数:18
相关论文
共 169 条
[1]   The proteasome: A suitable antineoplastic target [J].
Adams, J .
NATURE REVIEWS CANCER, 2004, 4 (05) :349-360
[2]   The development of proteasome inhibitors as anticancer drugs [J].
Adams, J .
CANCER CELL, 2004, 5 (05) :417-421
[3]   Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase [J].
Aghajan, Mariam ;
Jonai, Nao ;
Flick, Karin ;
Fu, Fei ;
Luo, Manlin ;
Cai, Xiaolu ;
Ouni, Ikram ;
Pierce, Nathan ;
Tang, Xiaobo ;
Lomenick, Brett ;
Damoiseaux, Robert ;
Hao, Rui ;
del Moral, Pierre M. ;
Verma, Rati ;
Li, Ying ;
Li, Cheng ;
Houk, Kendall N. ;
Jung, Michael E. ;
Zheng, Ning ;
Huang, Lan ;
Deshaies, Raymond J. ;
Kaiser, Peter ;
Huang, Jing .
NATURE BIOTECHNOLOGY, 2010, 28 (07) :738-U1750
[4]   The E3 Ubiquitin-Ligase Bmi1/Ring1A Controls the Proteasomal Degradation of Top2α Cleavage Complex - A Potentially New Drug Target [J].
Alchanati, Iris ;
Teicher, Carmit ;
Cohen, Galit ;
Shemesh, Vivian ;
Barr, Haim M. ;
Nakache, Philippe ;
Ben-Avraham, Danny ;
Idelevich, Anna ;
Angel, Itzchak ;
Livnah, Nurit ;
Tuvia, Shmuel ;
Reiss, Yuval ;
Taglicht, Daniel ;
Erez, Omri .
PLOS ONE, 2009, 4 (12)
[5]   Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells [J].
Altun, M ;
Galardy, PJ ;
Shringarpure, R ;
Hideshima, T ;
LeBlanc, R ;
Anderson, KC ;
Ploegh, HL ;
Kessler, BM .
CANCER RESEARCH, 2005, 65 (17) :7896-7901
[6]   Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies [J].
Bedford, Lynn ;
Hay, David ;
Devoy, Anny ;
Paine, Simon ;
Powe, Des G. ;
Seth, Rashmi ;
Gray, Trevor ;
Topham, Ian ;
Fone, Kevin ;
Rezvani, Nooshin ;
Mee, Maureen ;
Soane, Tim ;
Layfield, Robert ;
Sheppard, Paul W. ;
Ebendal, Ted ;
Usoskin, Dmitry ;
Lowe, James ;
Mayer, R. John .
JOURNAL OF NEUROSCIENCE, 2008, 28 (33) :8189-8198
[7]   The UPS and autophagy in chronic neurodegenerative disease Six of one and half a dozen of the other-or not? [J].
Bedford, Lynn ;
Paine, Simon ;
Rezvoni, Nooshin ;
Mee, Maureen ;
Lowe, James ;
Mayer, R. John .
AUTOPHAGY, 2009, 5 (02) :224-227
[8]   Is malfunction of the ubiquitin proteasome system the primary cause of α-synucleinopathies and other chronic human neurodegenerative disease? [J].
Bedford, Lynn ;
Hay, David ;
Paine, Simon ;
Rezvani, Nooshin ;
Mee, Maureen ;
Lowe, James ;
Mayer, R. John .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2008, 1782 (12) :683-690
[9]   A Tangled Web of Ubiquitin Chains: Breaking News in TNF-R1 Signaling [J].
Bianchi, Katiuscia ;
Meier, Pascal .
MOLECULAR CELL, 2009, 36 (05) :736-742
[10]   Conservation in the mechanism of nedd8 activation by the human AppBp1-Uba3 heterodimer [J].
Bohnsack, RN ;
Haas, AL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (29) :26823-26830