Intracellular Proteolysis and Neoplasia: Ubiquitin-Proteasome System, Cell Cycle, and Cancer

2020 ◽  
pp. 85-116
Author(s):  
Francisco Torrens ◽  
Gloria Castellano
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
System Cell ◽  
Intracellular Proteolysis

scholarly journals Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

2013 ◽  
Vol 31 (9) ◽  
pp. 1231-1238 ◽  
Author(s):  
Lindsey N. Micel ◽  
John J. Tentler ◽  
Peter G. Smith ◽  
Gail S. Eckhardt
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Regulation ◽  
Ubiquitin Chain ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Enzyme Families ◽  
And Function

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

scholarly journals The ubiquitin-proteasome system in glioma cell cycle control

Cell Division ◽  
2012 ◽  
Vol 7 (1) ◽  
pp. 18 ◽  
Author(s):  
Panagiotis J Vlachostergios ◽  
Ioannis A Voutsadakis ◽  
Christos N Papandreou
Keyword(s):  
Cell Cycle ◽  
Glioma Cell ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs that Enable Degradation

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5606
Author(s):  
Laura Márquez-Cantudo ◽  
Ana Ramos ◽  
Claire Coderch ◽  
Beatriz de Pascual-Teresa
Keyword(s):  
Cell Cycle ◽  
Hdac Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Protein Targets ◽  
E3 Ligases ◽  
Design And Synthesis ◽  
Ubiquitin Proteasome ◽  
Chromatin Packing ◽  
The Many ◽  
Cycle Regulation

Protein degradation by the Ubiquitin-Proteasome System is one of the main mechanisms of the regulation of cellular proteostasis, and the E3 ligases are the key effectors for the protein recognition and degradation. Many E3 ligases have key roles in cell cycle regulation, acting as checkpoints and checkpoint regulators. One of the many important proteins involved in the regulation of the cell cycle are the members of the Histone Deacetylase (HDAC) family. The importance of zinc dependent HDACs in the regulation of chromatin packing and, therefore, gene expression, has made them targets for the design and synthesis of HDAC inhibitors. However, achieving potency and selectivity has proven to be a challenge due to the homology between the zinc dependent HDACs. PROteolysis TArgeting Chimaera (PROTAC) design has been demonstrated to be a useful strategy to inhibit and selectively degrade protein targets. In this review, we attempt to summarize the E3 ligases that naturally ubiquitinate HDACs, analyze their structure, and list the known ligands that can bind to these E3 ligases and be used for PROTAC design, as well as the already described HDAC-targeted PROTACs.

The ubiquitin–proteasome system and cancer

2005 ◽  
Vol 41 ◽  
pp. 187-203 ◽  
Author(s):  
Anny Devoy ◽  
Tim Soane ◽  
Rebecca Welchman ◽  
R. John Mayer
Keyword(s):  
Cell Cycle ◽  
Protein Phosphorylation ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Cell Transformation ◽  
Ubiquitin Proteasome System ◽  
Regulatory Pathways ◽  
Regulatory Processes ◽  
Major Player ◽  
Ubiquitin Proteasome

The ubiquitin proteasome system (UPS) has emerged from obscurity to be seen as a major player in all regulatory processes in the cell. The concentrations of key proteins in diverse regulatory pathways are controlled by post-translational ubiquitination and degradation by the 26 S proteasome. These regulatory cascades include growth-factor-controlled signal-transduction pathways and multiple points in the cell cycle. The cell cycle is orchestrated by a combination of cyclin-dependent kinases, kinase inhibitors and protein phosphorylation, together with the timely and specific degradation of cyclins and kinase inhibitors at critical points in the cell cycle by the UPS. These processes provide the irreversibility needed for movement of the cycle through gap 1 (G1), DNA synthesis (S), gap 2 (G2) and mitosis (M). The molecular events include cell-size control, DNA replication, DNA repair, chromosomal rearrangements and cell division. It is doubtful whether these events could be achieved without the temporally and spatially regulated combination of protein phosphorylation and ubiquitin-dependent degradation of key cell-cycle regulatory proteins. The oncogenic transformation of cells is a multistep process that can be triggered by mutation of genes for proteins involved in regulatory processes from the cell surface to the nucleus. Since the UPS has critical functions at all these levels of control, it is to be expected that UPS activities will be central to cell transformation and cancer progression.

Intracellular Protein Degradation: From a Vague Idea thru the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Aaron Ciechanover
Keyword(s):  
Ubiquitin Proteasome System ◽  
Research Area ◽  
Regulation Of Transcription ◽  
Intracellular Protein ◽  
Cellular Processes ◽  
Intracellular Proteins ◽  
Broad Array ◽  
Intracellular Protein Degradation ◽  
Ubiquitin Proteasome ◽  
Intracellular Proteolysis

AbstractBetween the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely non-lysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs.

scholarly journals Regulation of the endothelial cell cycle by the ubiquitin-proteasome system

2009 ◽  
Vol 85 (2) ◽  
pp. 272-280 ◽  
Author(s):  
P. Fasanaro ◽  
M. C. Capogrossi ◽  
F. Martelli
Keyword(s):  
Cell Cycle ◽  
Endothelial Cell ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals Quantitative regulation of histone variant H2A.Z during cell cycle by ubiquitin proteasome system and SUMO-targeted ubiquitin ligases

2017 ◽  
Vol 81 (8) ◽  
pp. 1557-1560
Author(s):  
Daisuke Takahashi ◽  
Yuki Orihara ◽  
Saho Kitagawa ◽  
Masayuki Kusakabe ◽  
Takahiro Shintani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
Histone Variant ◽  
Ubiquitin Proteasome

scholarly journals The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression

2021 ◽  
Vol 22 (11) ◽  
pp. 5754
Author(s):  
Tingting Zou ◽  
Zhenghong Lin
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Ubiquitin Proteasome System ◽  
High Accumulation ◽  
Cancer Occurrence ◽  
Ubiquitin Proteasome ◽  
Cell Cycle Transition ◽  
Cycle Regulation ◽  
Cellular Components ◽  
Ubiquitination Machinery

The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell-cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), the activities of which are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors (CKIs). Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell-cycle process via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor proteins and oncoproteins or, inversely, abnormally high accumulation results in cell proliferation deregulation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the UPS machinery regulation of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell-cycle transition, cancer treatment, and the development of anti-cancer drugs.

scholarly journals Intracellular Dynamics of the Ubiquitin-Proteasome-System

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 367 ◽  
Author(s):  
Maisha Chowdhury ◽  
Cordula Enenkel
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Yeast Cells ◽  
Ubiquitin Chain ◽  
Dividing Cells ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome system is the major degradation pathway for short-lived proteins in eukaryotic cells. Targets of the ubiquitin-proteasome-system are proteins regulating a broad range of cellular processes including cell cycle progression, gene expression, the quality control of proteostasis and the response to geno- and proteotoxic stress. Prior to degradation, the proteasomal substrate is marked with a poly-ubiquitin chain. The key protease of the ubiquitin system is the proteasome. In dividing cells, proteasomes exist as holo-enzymes composed of regulatory and core particles. The regulatory complex confers ubiquitin-recognition and ATP dependence on proteasomal protein degradation. The catalytic sites are located in the proteasome core particle. Proteasome holo-enzymes are predominantly nuclear suggesting a major requirement for proteasomal proteolysis in the nucleus. In cell cycle arrested mammalian or quiescent yeast cells, proteasomes deplete from the nucleus and accumulate in granules at the nuclear envelope (NE) / endoplasmic reticulum ( ER) membranes. In prolonged quiescence, proteasome granules drop off the nuclear envelopeNE / ER membranes and migrate as droplet-like entitiesstable organelles  throughout the cytoplasm, as thoroughly investigated in yeast. When quiescence yeast cells are allowed to resume growth, proteasome granules clear and proteasomes are rapidly imported into the nucleus.Here, we summarize our knowledge about the enigmatic structure of proteasome storage granules and the trafficking of proteasomes and their substrates between the cyto- and nucleoplasm.Most of our current knowledge is based on studies in yeast. Their translation to mammalian cells promises to provide keen insight into protein degradation in non-dividing cells, which comprise the majority of our body’s cells.

Sign in / Sign up

Export Citation Format

Share Document