The Ubiquitin-Proteasome Pathway and Epigenetic Modifications in Cancer

2020 ◽  
Vol 21 (1) ◽  
pp. 20-32
Author(s):  
Azmi Yerlikaya ◽  
Ertan Kanbur ◽  
Bruce A. Stanley ◽  
Emrah Tümer
Keyword(s):  
Protein Quality ◽  
Genetic Alterations ◽  
Dna Methyltransferases ◽  
26S Proteasome ◽  
Cell Cycle Gene ◽  
Ubiquitin Proteasome Pathway ◽  
Pathological Conditions ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Almost All

Background: The ubiquitin-proteasome pathway is involved in almost all cellular processes (cell cycle, gene transcription and translation, cell survival and apoptosis, cell metabolism and protein quality control) mainly through the specific degradation of the majority of intracellular proteins (>80%) or partial processing of transcription factors (e.g., NF-κB). A growing amount of evidence now indicates that epigenetic changes are also regulated by the ubiquitin-proteasome pathway. Recent studies indicate that epigenetic regulations are equally crucial for almost all biological processes as well as for pathological conditions such as tumorigenesis, as compared to non-epigenetic control mechanisms (i.e., genetic alterations or classical signal transduction pathways). Objective: Here, we reviewed the recent work highlighting the interaction of the ubiquitin-proteasome pathway components (e.g., ubiquitin, E1, E2 and E3 enzymes and 26S proteasome) with epigenetic regulators (histone deacetylases, histone acetyltransferases and DNA methyltransferases). Results: Alterations in the regulation of the ubiquitin-proteasome pathway have been discovered in many pathological conditions. For example, a 2- to 32-fold increase in proteasomal activity and/or subunits has been noted in primary breast cancer cells. Although proteasome inhibitors have been successfully applied in the treatment of hematological malignancies (e.g., multiple myeloma), the clinical efficacy of the proteasomal inhibition is limited in solid cancers. Interestingly, recent studies show that the ubiquitin-proteasome and epigenetic pathways intersect in a number of ways through the regulation of epigenetic marks (i.e., acetylation, methylation and ubiquitylation). Conclusion: It is therefore believed that novel treatment strategies involving new generation ubiquitinproteasome pathway inhibitors combined with DNA methyltransferase, histone deacetylase or histone acetyltransferase inhibitors may produce more effective results with fewer adverse effects in cancer treatment as compared to standard chemotherapeutics in hematological as well as solid cancers.

Abstract 44: TAK1 Regulates Caspase 8 Activation and Necroptotic Signaling via Multiple Cell Death Checkpoints

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Xaioyun Guo ◽  
Haifeng Yin ◽  
Yi Chen ◽  
Lei Li ◽  
Jing Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Adaptor Protein ◽  
Regulatory Mechanisms ◽  
Caspase 8 ◽  
Ubiquitin Proteasome Pathway ◽  
Pathological Conditions ◽  
Ubiquitin Proteasome ◽  
Multiple Cell ◽  
Proteasome Pathway

Necroptosis has emerged as a new form of programmed cell death implicated in a number of pathological conditions such as ischemic injury, neurodegenerative disease, and viral infection. Recent studies indicate that TGFβ-activated kinase 1 (TAK1) is nodal regulator of necroptotic cell death, but the underlying molecular regulatory mechanisms remain elusive. Here we reported that TAK1 regulates necroptotic signaling as well as caspase 8 activation through both NFκB-dependent and -independent mechanisms. Inhibition of TAK1 promoted TNFα-induced necroptosis through the induction of RIP1 phosphorylation/activation and necrosome formation, in the presence of ongoing caspase activation. Further, inhibition of TAK1 triggered two caspase 8 activation pathways through the induction of RIP1-FADD-caspase 8 complex as well as FLIP cleavage/degradation. Mechanistically, our data uncovered an essential role of the adaptor protein TRADD in caspase 8 activation and necrosome formation triggered by TAK1 inhibition. Moreover, ablation of the deubiqutinase CYLD prevented both apoptotic and necroptotic signaling induced by TAK1 inhibition, whereas deletion of the E3 ubiquitin ligase TRAF2 had the opposite effect. Finally, blocking the ubiquitin-proteasome pathway prevented the degradation of key necroptotic signaling proteins and necrosome formation. Thus we identified novel regulatory mechanisms underling the critical role of TAK1 in necroptotic signaling through regulation of multiple cell death checkpoints. Targeting key components of the necroptotic pathway (e.g., TRADD and CYLD) and the ubiquitin-proteasome pathway may represent novel therapeutic strategies for pathological conditions driven by necroptosis.

Response of the ubiquitin-proteasome pathway to changes in muscle activity

2005 ◽  
Vol 288 (6) ◽  
pp. R1423-R1431 ◽  
Author(s):  
Michael B. Reid
Keyword(s):  
Muscle Activity ◽  
Mammalian Cells ◽  
Muscle Protein ◽  
Critical Role ◽  
26S Proteasome ◽  
Activity Increase ◽  
Pathway Activity ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The ubiquitin-proteasome pathway plays a critical role in the adaptation of skeletal muscle to persistent decreases or increases in muscle activity. This article outlines the basics of pathway function and reviews what we know about pathway responses to altered muscle use. The ubiquitin-proteasome pathway regulates proteolysis in mammalian cells by attaching ubiquitin polymers to damaged proteins; this targets the protein for degradation via the 26S proteasome. The pathway is constitutively active in muscle and continually regulates protein turnover. Conditions of decreased muscle use, e.g., unloading, denervation, or immobilization, stimulate general pathway activity. This activity increase is caused by upregulation of regulatory components in the pathway and leads to accelerated proteolysis, resulting in net loss of muscle protein. Pathway activity is also increased in response to exercise, a two-phase response. An immediate increase in selective ubiquitin conjugation by constitutive pathway components contributes to exercise-stimulated signal transduction. Over hours-to-days, exercise also stimulates a delayed increase in general ubiquitin conjugating activity by inducing expression of key components in the pathway. This increase mediates a late-phase rise in protein degradation that is required for muscle adaptation to exercise. Thus the ubiquitin-proteasome pathway functions as an essential mediator of muscle remodeling, both in atrophic states and exercise training.

Abstract 486: Down-regulation of type 1 cGMP-dependent Protein Kinase by the ubiquitin/proteasome pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
NUPUR DEY ◽  
Jennifer L Busch ◽  
Sharron H Francis ◽  
Jackie D Corbin ◽  
Thomas M Lincoln
Keyword(s):  
Protein Kinase ◽  
26S Proteasome ◽  
Down Regulation ◽  
Dependent Protein Kinase ◽  
Ubiquitin Proteasome Pathway ◽  
Cgmp Dependent Protein Kinase ◽  
Ubiquitin Proteasome ◽  
Dependent Protein ◽  
Proteasome Pathway

Type 1 cGMP-dependent protein kinase (PKG-I) is a widely expressed serine/threonine protein kinase, and is a major mediator of nitric oxide (NO) signaling in vascular smooth muscle cells (VSMC). PKG-I level is highly variable in VSMC and several studies have shown that atherogenic inflammatory cytokines lower the steady-statel levels of PKG-I. The mechanism of action of down-regulation is not well defined, but induction of type II NO synthase (iNOS) and subsequent persistent elevation of cGMP appear to contribute to PKG-I down regulation. In the present study, we examined the role of the ubiquitin/proteasome pathway in PKG-Iα down-regulation in response to elevated cGMP. Incubation of cultured VSMC with 8-Br-cGMP for 6–12 hr lowered PKG-I expression as assessed by western blotting. To further examine the mechanism, Cos7 cells, which do not express PKG-I mRNA or protein, were transfected with PKG-Iα/pcDNA vector and incubated with 8-Br-cGMP. 8-Br-cGMP suppressed PKG-Iα protein level in Cos7 cells (half-maximal concentration = 250 μM). Pretreatment of these cells with the proteasome inhibitor, MG132, followed by 8-Br-cGMP treatment prevented the decline suggesting the involvement of the ubiquitin/26S proteasome pathway. Immunoprecipitation of PKG-I followed by immunoblotting with anti-ubiquitin revealed multiple ubiquitinated PKG bands in the 8-Br-cGMP treated samples but not in untreated samples. Ubiquitination and down-regulation were also inhibited by the specific PKG-I catalytic inhibitor DT-2, suggesting the possible involvement of PKG autophosphorylation in the 8-Br-cGMP induced down-regulation. Mutation of the PKG-Iα autophosphorylation sites to alanines was performed to identify the phosphorylated site responsible for cGMP-dependent ubiquitination. In contrast to wild type PKG-Iα, PKG-Iα S64A, but not the S50A mutant, was not down-regulated by 8-Br-cGMP suggesting that autophosphorylation of serine-64 is required for the ubiquitination and down-regulation of PKG-I. Autophosphorylation and cGMP-mediated down-regulation of PKG-I may be an important mechanism to control excess cGMP signaling in VSMC.

scholarly journals The Xeroderma Pigmentosum Group E Gene Product DDB2 Is a Specific Target of Cullin 4A in Mammalian Cells

2001 ◽  
Vol 21 (20) ◽  
pp. 6738-6747 ◽  
Author(s):  
Alo Nag ◽  
Tanya Bondar ◽  
Shalu Shiv ◽  
Pradip Raychaudhuri
Keyword(s):  
Cell Cycle ◽  
Xeroderma Pigmentosum ◽  
Mammalian Cells ◽  
26S Proteasome ◽  
Breast Cancers ◽  
Ubiquitin Proteasome Pathway ◽  
Specific Target ◽  
Cullin 4A ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACT The damaged-DNA binding protein DDB consists of two subunits, DDB1 (127 kDa) and DDB2 (48 kDa). Mutations in the DDB2 subunit have been detected in patients suffering from the repair deficiency disease xeroderma pigmentosum (group E). In addition, recent studies suggested a role for DDB2 in global genomic repair. DDB2 also exhibits transcriptional activity. We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1. Here we show that DDB2 is a cell cycle-regulated protein. It is present at a low level in growth-arrested primary fibroblasts, and after release the level peaks at the G1/S boundary. The cell cycle regulation of DDB2 involves posttranscriptional mechanisms. Moreover, we find that an inhibitor of 26S proteasome increases the level of DDB2, suggesting that it is regulated by the ubiquitin-proteasome pathway. Our previous study indicated that the cullin family protein Cul-4A associates with the DDB2 subunit. Because cullins are involved in the ubiquitin-proteasome pathway, we investigated the role of Cul-4A in regulating DDB2. Here we show that DDB2 is a specific target of Cul-4A. Coexpression of Cul-4A, but not Cul-1 or other highly related cullins, increases the ubiquitination and the decay rate of DDB2. A naturally occurring mutant of DDB2 (2RO), which does not bind Cul-4A, is not affected by coexpression of Cul-4A. Studies presented here identify a specific function of the Cul-4A gene, which is amplified and overexpressed in breast cancers.

234. The ubiquitin-proteasome pathway in bovine and murine oocytes undergoing maturation

2005 ◽  
Vol 17 (9) ◽  
pp. 92
Author(s):  
P. C. Edgecumbe ◽  
M. D'Occhio ◽  
P. L. Kaye ◽  
M. Pantaleon
Keyword(s):  
Laser Scanning ◽  
Spindle Assembly Checkpoint ◽  
De Novo ◽  
Cyclin B1 ◽  
26S Proteasome ◽  
Meiotic Spindle ◽  
Confocal Laser ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Mammalian oocyte maturation is governed by an interaction between protein kinases, phosphatases and proteasases. Maturation promoting factor (MPF) is a serine/threonine kinase heterodimer composed of a catalytic cdc2/cdk1 subunit and a regulatory cyclin B1 subunit.1 Cyclin B1 undergoes rapid turnover via degradation in the ubiquitin-proteasome pathway (UPP) followed by de novo synthesis. A high level of MPF causes metaphase arrest, then UPP degradation of cyclin B1 allows the oocyte to exit metaphase I (MI). Proteasomes have been localised in pig and rat oocytes. Although in both species they are associated with the MI and MII meiotic spindles, immunostaining at the germinal vesicle (GV) stage is different with perinuclear staining in rat GV and intra-GV staining in the pig. This may suggest different roles for proteasomes prior to GV breakdown (GVBD) in different species. This study used confocal laser scanning immunohistochemistry with a specific antiserum against the 20S proteolytic ‘core’ of the 26S proteasome to reveal proteasomes in murine oocytes undergoing maturation in vitro. In the mouse, proteasomes were associated with the meiotic spindle, similar to observations in pig and rat oocytes and preliminary studies in the bovine suggest a similar immunolocalisation. Cyclin B1 also accumulates around the spindle during meiosis.1 This suggests that proteasomes are prevented from degrading cyclin B1 until the MI-AI and MII-AII transitions. Immunolabelling showed Fam, a deubiquitinylating enzyme (also known as Usp9x) was localised at the spindle during MI and MII. This suggests a link between Fam, the UPP and the spindle assembly checkpoint to prevent cyclin B1 degradation until required. (1)Huo LJ, Fan HY, Zhong ZS, Chen DY, Schatten H, Sun QY. (2004). Ubiquitin-proteasome pathway modulates mouse oocyte meiotic maturation and fertilization via regulation of MAPK cascade and cyclin B1 degradation. Mech. Dev. 121, 1275–1287.

scholarly journals Proteasome inhibitors: new class of antitumor agents

2003 ◽  
Vol 3 (4) ◽  
pp. 5-10
Author(s):  
Gordan Srkalović
Keyword(s):  
Antitumor Agents ◽  
Proteasome Inhibitors ◽  
26S Proteasome ◽  
Ubiquitin Proteasome Pathway ◽  
Cellular Processes ◽  
New Class ◽  
C Terminus ◽  
Ubiquitin Conjugating Enzyme ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The ubiquitin-proteasome pathway is the principal pathway for intracellular protein degradation1,2 (Fig 1). This pathway selectively degrades an extensive number of short-lived regulatory proteins involved in the control of normal cellular processes. In order to be degraded, proteins targeted by the ubiquitin-proteasome pathway are covalently tagged by polyubiquitination, via a three-step enzymatic process, which ultimately leads to their recognition and degradation, by the 26S proteasome in a highly specific and regulated manner. This process is accomplished by the sequential action of three enzymes: an ATP-dependent ubiquitin-activating enzyme (E1), an ubiquitin-conjugating enzyme (E2) and an ubiquitin-pro-tein ligase (E3).3 This cascade covalently links the C terminus of ubiquitin to a free amino group on the target protein, usually the ε-amino of a lysine residue.

scholarly journals Characterization of Arabidopsis thaliana R2R3 S23 MYB Transcription Factors as Novel Targets of the Ubiquitin Proteasome-Pathway and Regulators of Salt Stress and Abscisic Acid Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Chase Beathard ◽  
Sutton Mooney ◽  
Raed Al-Saharin ◽  
Aymeric Goyer ◽  
Hanjo Hellmann
Keyword(s):  
Transcription Factor ◽  
Abscisic Acid ◽  
Salt Stress ◽  
Abiotic Stress ◽  
Expression Patterns ◽  
26S Proteasome ◽  
E3 Ligases ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Rapid response to environmental changes and abiotic stress to coordinate developmental programs is critical for plants. To accomplish this, plants use the ubiquitin proteasome pathway as a flexible and efficient mechanism to control protein stability and to direct cellular reactions. Here, we show that all three members of the R2R3 S23 MYB transcription factor subfamily, MYB1, MYB25, and MYB109, are degraded by the 26S proteasome, likely facilitated by a CUL3-based E3 ligase that uses MATH-BTB/POZ proteins as substrate adaptors. A detailed description of MYB1, MYB25, and MYB109 expression shows their nuclear localization and specific tissue specific expression patterns. It further demonstrates that elevated expression of MYB25 reduces sensitivities toward abscisic acid, osmotic and salt stress in Arabidopsis, while downregulation of all S23 members results in hypersensitivities. Transcriptional profiling in root and shoot of seedlings overexpressing MYB25 shows that the transcription factor widely affects cellular stress pathways related to biotic and abiotic stress control. Overall, the work extends our knowledge on proteins targeted by CUL3-based E3 ligases that use MATH-BTB/POZ proteins as substrate adaptors and provides first information on all members of the MYB S23 subfamily.

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