Regulation of Autophagic Flux by the 20S Proteasome

Njomen, Evert; Tepe, Jetze J.

doi:10.1016/j.chembiol.2019.07.002

Cited by 30 publications

(21 citation statements)

References 61 publications

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“…Findings also indicate a mechanism of crosstalk between the proteasome and autophagy pathway [65][66][67][68][69]. This includes the degradation of synaptosomal-associated protein 29 (SNAP29) and syntaxin 17 (STX17) by the ubiquitin-independent 20S proteasome [70].…”

Section: The Ups and Tumor Metabolismmentioning

confidence: 91%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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Section: The Ups and Tumor Metabolismmentioning

confidence: 91%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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“…[27] These imidazoline derivatives had been commenced as ligands in transition metal-catalyzed processes. [28] The reaction was initiated by the formation of an intermediate amide (10) from the ferrocene containing carboxylic acid (8) and the diamine (9). Next, the reaction utilized a bis(triphenyl) oxodiphosphonium trifluoromethanesulfonate mediated cyclodehydration of the amide to generate imidazolines in excellent yields.…”

Section: Methods A: Synthesis Of Imidazolines From 12-diaminesmentioning

confidence: 99%

“…After the discovery of the imidazoline binding site (IBS) in 1984, [4] the synthesis of imidazoline containing compounds has increased significantly. Furthermore, various substituted imidazolines have illustrated potential therapeutic value for the treatment of different diseases as antihelminthics, [5] antifungal, [6] antitumor, [7] hypertension, [8] hyperglycemia, [9] as well as for the potential treatment of Parkinson's, [10] and Alzheimer's disease. [11] In addition, imidazolines have been used as chiral catalysts, [12] transition metal ligands [13] and as different synthetic intermediates.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Synthesis of Imidazolines (2009–2020)

Mehedi

Tepe

2020

Adv Synth Catal

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Imidazoline is an important class of compounds found in numerous natural and pharmaceutical products. The compounds are also used as an intermediate in the synthesis of organic molecules. Moreover, chiral imidazolines are widely utilized as organocatalysts to synthesize various natural and synthetic organic compounds. In the past decade, there was an increase in interest in developing new methods to synthesize these imidazoline analogs. Both modification of the previously established methods and the development of new methods are carried out significantly. This review article highlights the progress of the synthesis of imidazoline scaffolds in the last few years (2009-present). The review also described the proposed mechanism illustrated in many of the reports.

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“…25 TCH-165 and other 20S activators identified in our lab were reported to only enhance the degradation of endogenous 20S substrates. 25,28 Structured proteins normally targeted by the 26S-ubiquitin-dependent proteasome system were not affected. To determine the Active Concentration (AC) at which TCH-165 doubles (200%) 20S activity (referred to hereafter as AC200), and the maximum fold enhancement of 20S activity (referred to hereafter as Fold M ), the hydrolysis of canonical proteasome peptide substrates ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

Njomen

Lansdell

Vanecek

et al. 2020

Preprint

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Enhancing proteasome activity is a potential new therapeutic strategy to prevent the accumulation of aberrant high levels of protein that drive the pathogenesis of many diseases. Herein, we examine the use of small mole-cules to activate the 20S proteasome to reduce aberrant signaling by the undruggable oncoprotein c-MYC, to treat c-MYC driven oncogenesis. Overexpression of c-MYC is found in more than 50% of all human cancer but remains undruggable because of its highly dynamic intrinsically disordered 3-D conformation, which renders traditional therapeutic strategies largely ineffective. We demonstrate herein that small molecule activation of the 20S proteasome targets dysregulated intrinsically disordered proteins (IDPs), including c-MYC, and reduces can-cer growth in vitro and in vivo models of multiple myeloma, and is even effective in bortezomib resistant cells and unresponsive patient samples. Genomic analysis of various cancer pathways showed that proteasome activation results in downregulation of many c-MYC target genes. Moreover, proteasome enhancement was well tolerated in mice and dogs. These data support the therapeutic potential of 20S proteasome activation in tar-geting IDP-driven proteotoxic disorders, including cancer, and demonstrate that this new therapeutic strategy is well tolerated in vivo.

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Regulation of Autophagic Flux by the 20S Proteasome

Cited by 30 publications

References 61 publications

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Recent Advances in the Synthesis of Imidazolines (2009–2020)

Enhancing c-MYC degradation via 20S proteasome activation inducesin vivoanti-tumor efficacy

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