The Ubiquitin-Proteasome Pathway and Its Role in Cancer

2005 ◽  
Vol 23 (21) ◽  
pp. 4776-4789 ◽  
Author(s):  
Aparna Mani ◽  
Edward P. Gelmann
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
De Novo ◽  
Cell Cancer ◽  
26S Proteasome ◽  
Great Promise ◽  
Major Pathway ◽  
Cellular Processes ◽  
Wide Range

Critical cellular processes are regulated, in part, by maintaining the appropriate intracellular levels of proteins. Whereas de novo protein synthesis is a comparatively slow process, proteins are rapidly degraded at a rate compatible with the control of cell cycle transitions and cell death induction. A major pathway for protein degradation is initiated by the addition of multiple 76–amino acid ubiquitin monomers via a three-step process of ubiquitin activation and substrate recognition. Polyubiquitination targets proteins for recognition and processing by the 26S proteasome, a cylindrical organelle that recognizes ubiquitinated proteins, degrades the proteins, and recycles ubiquitin. The critical roles played by ubiquitin-mediated protein turnover in cell cycle regulation makes this process a target for oncogenic mutations. Oncogenes of several common malignancies, for example colon and renal cell cancer, code for ubiquitin ligase components. Cervical oncogenesis by human papillomavirus is also mediated by alteration of ubiquitin ligase pathways. Protein degradation pathways are also targets for cancer therapy, as shown by the successful introduction of bortezomib, an inhibitor of the 26S proteasome. Further work in this area holds great promise toward our understanding and treatment of a wide range of cancers.

scholarly journals Some assembly required: dedicated chaperones in eukaryotic proteasome biogenesis

2008 ◽  
Vol 389 (9) ◽  
Author(s):  
Andrew R. Kusmierczyk ◽  
Mark Hochstrasser
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Self Assembly ◽  
26S Proteasome ◽  
Misfolded Proteins ◽  
Cellular Processes ◽  
Intracellular Proteins ◽  
Assembly Factors ◽  
The Many ◽  
Complicated Task

Abstract The 26S proteasome is the key eukaryotic protease responsible for the degradation of intracellular proteins. Protein degradation by the 26S proteasome plays important roles in numerous cellular processes, including the cell cycle, differentiation, apoptosis, and the removal of damaged or misfolded proteins. How this 2.5-MDa complex, composed of at least 32 different polypeptides, is assembled in the first place is not well understood. However, it has become evident that this complicated task is facilitated by a framework of protein factors that chaperone the nascent proteasome through its various stages of assembly. We review here the known proteasome-specific assembly factors, most only recently discovered, and describe their potential roles in proteasome assembly, with an emphasis on the many remaining unanswered questions about this intricate process of assisted self-assembly.

scholarly journals Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle

2012 ◽  
Vol 23 (21) ◽  
pp. 4203-4211 ◽  
Author(s):  
Dong-Hwan Kim ◽  
Deanna M. Koepp
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
S Phase ◽  
Temperature Sensitive ◽  
Dependent Manner ◽  
Charged Residues ◽  
Phase Progression ◽  
Positively Charged

The ubiquitin proteasome system plays a pivotal role in controlling the cell cycle. The budding yeast F-box protein Dia2 is required for genomic stability and is targeted for ubiquitin-dependent degradation in a cell cycle–dependent manner, but the identity of the ubiquitination pathway is unknown. We demonstrate that the Hect domain E3 ubiquitin ligase Tom1 is required for Dia2 protein degradation. Deletion of DIA2 partially suppresses the temperature-sensitive phenotype of tom1 mutants. Tom1 is required for Dia2 ubiquitination and degradation during G1 and G2/M phases of the cell cycle, whereas the Dia2 protein is stabilized during S phase. We find that Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase, suggesting a mechanism for this proteolytic switch. Tom1 recognizes specific, positively charged residues in a Dia2 degradation/NLS domain. Loss of these residues blocks Tom1-mediated turnover of Dia2 and causes a delay in G1–to–S phase progression. Deletion of DIA2 rescues a delay in the G1–to–S phase transition in the tom1Δ mutant. Together our results suggest that Tom1 targets Dia2 for degradation during the cell cycle by recognizing positively charged residues in the Dia2 degradation/NLS domain and that Dia2 protein degradation contributes to G1–to–S phase progression.

Artificial protein assemblies with well-defined supramolecular protein nanostructures

2021 ◽  
Author(s):  
Suyeong Han ◽  
Yongwon Jung
Keyword(s):  
Vaccine Development ◽  
De Novo ◽  
Building Blocks ◽  
Protein Assembly ◽  
Protein Assemblies ◽  
Cellular Processes ◽  
Wide Range ◽  
Array Structures ◽  
Small Chemical ◽  
Artificial Protein

Nature uses a wide range of well-defined biomolecular assemblies in diverse cellular processes, where proteins are major building blocks for these supramolecular assemblies. Inspired by their natural counterparts, artificial protein-based assemblies have attracted strong interest as new bio-nanostructures, and strategies to construct ordered protein assemblies have been rapidly expanding. In this review, we provide an overview of very recent studies in the field of artificial protein assemblies, with the particular aim of introducing major assembly methods and unique features of these assemblies. Computational de novo designs were used to build various assemblies with artificial protein building blocks, which are unrelated to natural proteins. Small chemical ligands and metal ions have also been extensively used for strong and bio-orthogonal protein linking. Here, in addition to protein assemblies with well-defined sizes, protein oligomeric and array structures with rather undefined sizes (but with definite repeat protein assembly units) also will be discussed in the context of well-defined protein nanostructures. Lastly, we will introduce multiple examples showing how protein assemblies can be effectively used in various fields such as therapeutics and vaccine development. We believe that structures and functions of artificial protein assemblies will be continuously evolved, particularly according to specific application goals.

scholarly journals The role of SCF ubiquitin-ligase complex at the beginning of life

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Jiayan Xie ◽  
Yimei Jin ◽  
Guang Wang
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Cellular Proteins ◽  
Cell Cycle Regulators ◽  
Signal Transducers ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin Ligase Complex ◽  
Scf Ubiquitin Ligase

AbstractAs the largest family of E3 ligases, the Skp1-cullin 1-F-box (SCF) E3 ligase complex is comprised of Cullins, Skp1 and F-box proteins. And the SCF E3 ubiquitin ligases play an important role in regulating critical cellular processes, which promote degradation of many cellular proteins, including signal transducers, cell cycle regulators, and transcription factors. We review the biological roles of the SCF ubiquitin-ligase complex in gametogenesis, oocyte-to-embryo transition, embryo development and the regulation for estrogen and progestin. We find that researches about the SCF ubiquitin-ligase complex at the beginning of life are not comprehensive, thus more in-depth researches will promote its eventual clinical application.

scholarly journals The Role of Selective Protein Degradation in the Regulation of Iron and Sulfur Homeostasis in Plants

2020 ◽  
Vol 21 (8) ◽  
pp. 2771 ◽  
Author(s):  
Anna Wawrzyńska ◽  
Agnieszka Sirko
Keyword(s):  
Protein Degradation ◽  
Plant Development ◽  
Sulfur Metabolism ◽  
High Energy ◽  
26S Proteasome ◽  
Control Mechanisms ◽  
Wide Range ◽  
Ubiquitin Conjugation ◽  
Cellular Components

Plants are able to synthesize all essential metabolites from minerals, water, and light to complete their life cycle. This plasticity comes at a high energy cost, and therefore, plants need to tightly allocate resources in order to control their economy. Being sessile, plants can only adapt to fluctuating environmental conditions, relying on quality control mechanisms. The remodeling of cellular components plays a crucial role, not only in response to stress, but also in normal plant development. Dynamic protein turnover is ensured through regulated protein synthesis and degradation processes. To effectively target a wide range of proteins for degradation, plants utilize two mechanistically-distinct, but largely complementary systems: the 26S proteasome and the autophagy. As both proteasomal- and autophagy-mediated protein degradation use ubiquitin as an essential signal of substrate recognition, they share ubiquitin conjugation machinery and downstream ubiquitin recognition modules. Recent progress has been made in understanding the cellular homeostasis of iron and sulfur metabolisms individually, and growing evidence indicates that complex crosstalk exists between iron and sulfur networks. In this review, we highlight the latest publications elucidating the role of selective protein degradation in the control of iron and sulfur metabolism during plant development, as well as environmental stresses.

scholarly journals Identification of Z nucleotides as an ancient signal for two-component system activation in bacteria

2020 ◽  
Vol 117 (52) ◽  
pp. 33530-33539
Author(s):  
Oscar J. Vázquez-Ciros ◽  
Adrián F. Alvarez ◽  
Dimitris Georgellis
Keyword(s):  
De Novo ◽  
Response Regulator ◽  
Phosphoryl Group ◽  
Response Regulators ◽  
Carbamoyl Phosphate ◽  
Cellular Processes ◽  
Wide Range ◽  
Two Component ◽  
Two Component Systems

Two-component systems (TCSs) in bacteria are molecular circuits that allow the perception of and response to diverse stimuli. These signaling circuits rely on phosphoryl-group transfers between transmitter and receiver domains of sensor kinase and response regulator proteins, and regulate several cellular processes in response to internal or external cues. Phosphorylation, and thereby activation, of response regulators has been demonstrated to occur by their cognate histidine kinases but also by low molecular weight phosphodonors such as acetyl phosphate and carbamoyl phosphate. Here, we present data indicating that the intermediates of the de novo syntheses of purines and histidine, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5′-monophosphate (ZMP) and/or 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5′-triphosphate (ZTP), activate the response regulator UvrY, by promoting its autophosphorylation at the conserved aspartate at position 54. Moreover, these Z nucleotides are shown to also activate the nonrelated response regulators ArcA, CpxR, RcsB, and PhoQ. We propose that ZMP and/or ZTP act as alarmones for a wide range of response regulators in vivo, providing a novel mechanism by which they could impact gene expression in response to metabolic cues.

scholarly journals Regulating protein breakdown through proteasome phosphorylation

2017 ◽  
Vol 474 (19) ◽  
pp. 3355-3371 ◽  
Author(s):  
Jordan J.S. VerPlank ◽  
Alfred L. Goldberg
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Protein Degradation ◽  
Mammalian Cells ◽  
Calcium Influx ◽  
Great Majority ◽  
Adenosine Monophosphate ◽  
Guanosine Monophosphate ◽  
26S Proteasome ◽  
Degradation Rates

The ubiquitin proteasome system degrades the great majority of proteins in mammalian cells. Countless studies have described how ubiquitination promotes the selective degradation of different cell proteins. However, there is a small but growing literature that protein half-lives can also be regulated by post-translational modifications of the 26S proteasome. The present study reviews the ability of several kinases to alter proteasome function through subunit phosphorylation. For example, PKA (protein kinase A) and DYRK2 (dual-specificity tyrosine-regulated kinase 2) stimulate the proteasome's ability to degrade ubiquitinated proteins, peptides, and adenosine triphosphate, while one kinase, ASK1 (apoptosis signal-regulating kinase 1), inhibits proteasome function during apoptosis. Proteasome phosphorylation is likely to be important in regulating protein degradation because it occurs downstream from many hormones and neurotransmitters, in conditions that raise cyclic adenosine monophosphate or cyclic guanosine monophosphate levels, after calcium influx following synaptic depolarization, and during phases of the cell cycle. Beyond its physiological importance, pharmacological manipulation of proteasome phosphorylation has the potential to combat various diseases. Inhibitors of phosphodiesterases by activating PKA or PKG (protein kinase G) can stimulate proteasomal degradation of misfolded proteins that cause neurodegenerative or myocardial diseases and even reduce the associated pathology in mouse models. These observations are promising since in many proteotoxic diseases, aggregation-prone proteins impair proteasome function, and disrupt protein homeostasis. Conversely, preventing subunit phosphorylation by DYRK2 slows cell cycle progression and tumor growth. However, further research is essential to determine how phosphorylation of different subunits by these (or other) kinases alters the properties of this complex molecular machine and thus influence protein degradation rates.

scholarly journals Role of the UBL-UBA Protein KPC2 in Degradation of p27 at G1 Phase of the Cell Cycle

2005 ◽  
Vol 25 (21) ◽  
pp. 9292-9303 ◽  
Author(s):  
Taichi Hara ◽  
Takumi Kamura ◽  
Shuhei Kotoshiba ◽  
Hidehisa Takahashi ◽  
Kenichiro Fujiwara ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Kinase Inhibitor ◽  
26S Proteasome ◽  
G1 Phase ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Uba Domain

ABSTRACT KPC2 (Kip1 ubiquitylation-promoting complex 2) together with KPC1 forms the ubiquitin ligase KPC, which regulates degradation of the cyclin-dependent kinase inhibitor p27 at the G1 phase of the cell cycle. KPC2 contains a ubiquitin-like (UBL) domain, two ubiquitin-associated (UBA) domains, and a heat shock chaperonin-binding (STI1) domain. We now show that KPC2 interacts with KPC1 through its UBL domain, with the 26S proteasome through its UBL and NH2-terminal UBA domains, and with polyubiquitylated proteins through its UBA domains. The association of KPC2 with KPC1 was found to stabilize KPC1 in a manner dependent on the STI1 domain of KPC2. KPC2 mutants that lacked either the NH2-terminal or the COOH-terminal UBA domain supported the polyubiquitylation of p27 in vitro, whereas a KPC2 derivative lacking the STI1 domain was greatly impaired in this regard. Depletion of KPC2 by RNA interference resulted in inhibition of p27 degradation at the G1 phase, and introduction of KPC2 derivatives into the KPC2-depleted cells revealed that the NH2-terminal UBA domain of KPC2 is essential for p27 degradation. These observations suggest that KPC2 cooperatively regulates p27 degradation with KPC1 and that the STI1 domain as well as the UBL and UBA domains of KPC2 are indispensable for its function.

scholarly journals In vitro cell cycle oscillations exhibit a robust and hysteretic response to changes in cytoplasmic density

2021 ◽  
Author(s):  
Minjun Jin ◽  
Franco Tavella ◽  
Shiyuan Wang ◽  
Qiong Yang
Keyword(s):  
Cell Cycle ◽  
Oscillatory Behavior ◽  
Cycle Number ◽  
Biochemical Processes ◽  
Cellular Processes ◽  
Wide Range ◽  
A Cell ◽  
Xenopus Egg ◽  
Number Of Cycles

Cells control the properties of the cytoplasm to ensure the proper functioning of biochemical processes. Recent studies showed that the density of the cytoplasm varies in both physiological and pathological states of cells undergoing growth, division, differentiation, apoptosis, senescence, and metabolic starvation. Little is known about how cellular processes cope with these cytoplasmic variations. Here we study how a cell cycle oscillator comprising cyclin-dependent kinase (CDK1) responds to cytoplasmic density changes by systematically diluting or concentrating a cycling Xenopus egg cytoplasm in cell-like microfluidic droplets. We found that the cell cycle maintains robust oscillations over a wide range of deviations from the endogenous density by as low as 0.2x to more than 1.22x. A further dilution or concentration from these values will arrest the system in a low or high steady-state of CDK1 activity, respectively. Interestingly, diluting a concentrated arrested cytoplasm recovers its oscillatory behavior but requires a significantly lower concentration than 1.22x. Thus, the cell cycle switches reversibly between oscillatory and stable steady states at distinct thresholds depending on the direction of density tuning, forming a hysteresis loop. We recapitulated these observations by a mathematical model. The model predicted that Wee1 and Cdc25 positive feedback do not contribute to the observed robustness, confirmed by experiments. Nevertheless, modulating these feedback strengths and cytoplasmic density changes the total number of cycles, revealing a new role of Wee1 and Cdc25 in controlling the cycle number of early embryonic extracts. Our system can be applied to study how cytoplasmic density affects other cellular processes.

Histiocytic Sarcoma in the Kidney: A Rare Presentation

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S72-S72
Author(s):  
Priya Johal
Keyword(s):  
De Novo ◽  
Cell Cancer ◽  
Histiocytic Sarcoma ◽  
Unknown Etiology ◽  
Rare Presentation ◽  
Transplant Patients ◽  
Clinical Presentations ◽  
Eosinophilic Cytoplasm ◽  
Wide Range ◽  
History Of

Abstract Background Histiocytic sarcoma is a rare neoplasm of mature histiocytes with a wide range of clinical presentations and manifestations. The heterogeneity of this neoplasm can cause difficulty in both diagnosis and treatment. It is a diagnosis of exclusion, requiring verification of the histiocytic lineage and the exclusion of other B-cell related malignancies. Although cases of postrenal transplant histiocytic sarcoma have been reported, incidences in a native kidney are rare. Case Report We present the case of a 70-year-old male with a history of colorectal adenocarcinoma, status post chemotherapy, with an incidental exophytic renal mass found on imaging, which was determined to be a sarcomatoid renal cell cancer on biopsy. Radical nephrectomy was performed, revealing a 4.5 × 3.5 × 3.2-cm mass invading the renal pelvis and fat. Microscopic examination of the tumor showed large, poorly cohesive neoplastic cells with abundant pale, eosinophilic cytoplasm that stained positive for vimentin, CD4, CD163, and CD68 and weakly/focally positive for lysozyme. Negative immunostains included PAX-8, pan-CK, AE1/AE3, HMB45, S100, CD34, CD30, ALK1, CD1a, myeloperoxidase, CD138, myo-D1, SMA, and CD21. A diagnosis of histiocytic sarcoma, grade 4 was made based on these findings. Discussion Histiocytic sarcoma is a disease of unknown etiology accounting for less than 1% of all hematolymphoid neoplasms. Our literature review revealed no other cases arising de novo in the kidney, but several cases were reported in postrenal transplant patients. Diagnosis of histiocytic sarcoma is difficult as it is a diagnosis of exclusion. The immunohistochemical profile most often expresses lysosome-related markers, such as CD68, CD163, or lysozyme. Additionally, negative staining is expected for markers related to B cells, T cells, and melanocytes. The cells are often large with eosinophilic cytoplasm, well-defined borders, and vesicular chromatin. Although there are numerous differentials, distinct morphologic and immunohistochemical features allow for accurate diagnosis.

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