Dynamic regulation of ubiquitin-dependent cell cycle control

Craney, Allison; Rapé, Michael

doi:10.1016/j.ceb.2013.07.004

Cited by 36 publications

(30 citation statements)

References 77 publications

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“…Among the various PTMs, ubiquitination, a covalent attachment of a 76 amino acid protein ubiquitin, is of utmost importance. This PTM regulates a broad spectrum of intracellular processes including molecular biodistribution, protein kinase activity, DNA damage response (DDR), chromatin organization and dynamics, gene expression, cell cycle and death [1][2][3][4][5]. Markedly, through proteasome/lysosome-mediated destruction of key signal transduction regulators, ubiquitination is capable of modulating activities and even shutting down entire signal transduction networks.…”

Section: Introductionmentioning

confidence: 99%

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Zou

Levy-Cohen

Blank

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

106

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Section: Introductionmentioning

confidence: 99%

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Zou

Levy-Cohen

Blank

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

106

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“…Regulated degradation mediated by the ubiquitin-proteasome system (UPS) 3 is an important post-translational mechanism that helps to achieve precise fine-tuning of protein levels and is being increasingly linked to more and more pathways. The UPS is the major intracellular degradation pathway that has evolved into a complex system consisting of several hundred dedicated components (1).…”

mentioning

confidence: 99%

“…cyclins, cyclin-dependent kinase inhibitors, etc.) that need to be degraded or inactivated before cell cycle checkpoint mechanisms decide upon progress (2,3). Transcription factors (e.g.…”

mentioning

confidence: 99%

Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System

Guharoy

Bhowmick

Tompa

2016

Journal of Biological Chemistry

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The ubiquitin-proteasome system (UPS) regulates diverse cellular pathways by the timely removal (or processing) of proteins. Here we review the role of structural disorder and conformational flexibility in the different aspects of degradation. First, we discuss post-translational modifications within disordered regions that regulate E3 ligase localization, conformation, and enzymatic activity, and also the role of flexible linkers in mediating ubiquitin transfer and reaction processivity. Next we review well studied substrates and discuss that substrate elements (degrons) recognized by E3 ligases are highly disordered: short linear motifs recognized by many E3s constitute an important class of degrons, and these are almost always present in disordered regions. Substrate lysines targeted for ubiquitination are also often located in neighboring regions of the E3 docking motifs and are therefore part of the disordered segment. Finally, biochemical experiments and predictions show that initiation of degradation at the 26S proteasome requires a partially unfolded region to facilitate substrate entry into the proteasomal core.Many cellular pathways and regulatory networks require spatial and temporal control of effector protein levels. Regulated degradation mediated by the ubiquitin-proteasome system (UPS) 3 is an important post-translational mechanism that helps to achieve precise fine-tuning of protein levels and is being increasingly linked to more and more pathways. The UPS is the major intracellular degradation pathway that has evolved into a complex system consisting of several hundred dedicated components (1). Important examples of regulated degradation include cell cycle regulatory proteins (e.g. cyclins, cyclin-dependent kinase inhibitors, etc.) that need to be degraded or inactivated before cell cycle checkpoint mechanisms decide upon progress (2, 3). Transcription factors (e.g. mammalian Myc, Jun, E2-F, p53, etc.) that activate gene expression triggered by specific stimuli are usually maintained at low levels (4, 5); further, the ubiquitin system also triggers processing (by limited proteolysis) and activation of transcription factors such as NFB (6). Cell surface growth factor/hormone receptors undergo internalization and degradation to switch off signaling inputs (7-12). The UPS also tightly regulates other key intracellular effectors (e.g. Smad proteins, Bcl-2) of signaling pathways (13-15). Not surprisingly, defects in regulated degradation are being linked to increasing numbers of diseases, including neurodegeneration and cancer, making the UPS very attractive for drug design (16 -19).Ubiquitination is organized as a cascade of E1 (ubiquitinactivating), E2 (ubiquitin-conjugating), and E3 (ubiquitin ligase) enzymes. The pathway is strongly conserved from yeast to mammals. The E1-E2-E3 axis has a pyramidal structure, with 2 E1 proteins (in humans), 30 -40 E2 enzymes, and Ͼ600 E3 ligases (20). E3s are subclassified into major groups based on their subunit organization and domain composition ( Fig. 1) (21,...

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“…The CRLs and APC/C are active during different phases of the cell cycle and regulate critical cellular events through degradative ubiquitination. These functions are discussed in greater detail in other reviews [92,93]. …”

Section: Introductionmentioning

confidence: 99%

Specificity and disease in the ubiquitin system

Chaugule

Walden

2016

Biochemical Society Transactions

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Post-translational modification (PTM) of proteins by ubiquitination is an essential cellular regulatory process. Such regulation drives the cell cycle and cell division, signalling and secretory pathways, DNA replication and repair processes and protein quality control and degradation pathways. A huge range of ubiquitin signals can be generated depending on the specificity and catalytic activity of the enzymes required for attachment of ubiquitin to a given target. As a consequence of its importance to eukaryotic life, dysfunction in the ubiquitin system leads to many disease states, including cancers and neurodegeneration. This review takes a retrospective look at our progress in understanding the molecular mechanisms that govern the specificity of ubiquitin conjugation.

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Dynamic regulation of ubiquitin-dependent cell cycle control

Cited by 36 publications

References 77 publications

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System

Specificity and disease in the ubiquitin system

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