Small-Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System

Background: The 26S proteasome is a proteolytic complex of multimeric protease, which operates at the executive end of the Ubiquitin-Proteasome System (UPS) and degrades the polyubiquitylated proteins. Methods: After a brief introduction of 26S proteasome and Ubiquitin-Proteasome System (UPS), this review focuses on the structure and function of the 26S proteasome in intracellular protein level regulation. Then, physiological regulation mechanisms and processes are elaborated. In addition, the advantages and defects of approved 26S proteasome inhibitors were discussed. Finally, we summarized the novel peptide 26S proteasome inhibitors according to their structural classifications, highlighting their design strategies, inhibitory activity and Structure-Activity Relationships (SARs). Results: Cellular function maintenance relies on the proteasome metabolizing intracellular proteins to control intracellular protein levels, which is especially important for cancer cells to survive and proliferate. In primary tumors, proteasomes had a higher level and more potent activity. Currently, the approved small peptide inhibitors have proved their specific 26S proteasome inhibitory effects and considerable antitumor activities, but with obvious defects. Increasingly, novel peptide inhibitors are emerging and possess promising values in cancer therapy. Conclusion: Overall, the 26S proteasome is an efficient therapeutic target and novel 26S proteasome inhibitors hold potency for cancer therapy.

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Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Cancers ◽

10.3390/cancers13123079 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3079

Author(s):

Gabriel LaPlante ◽

Wei Zhang

Keyword(s):

Protein Degradation ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Proteasome Inhibitors ◽

Cancer Therapeutics ◽

Ubiquitin Proteasome System ◽

Cellular Protein ◽

E3 Ligases ◽

Protein Levels ◽

Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.

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Intracellular Protein Degradation: From a Vague Idea, Through the Lysosome and the Ubiquitin—Proteasome System, and onto Human Diseases and Drug Targeting (Nobel Lecture)

ChemInform ◽

10.1002/chin.200549272 ◽

2005 ◽

Vol 36 (49) ◽

Author(s):

Aaron Ciechanover

Keyword(s):

Protein Degradation ◽

Drug Targeting ◽

Ubiquitin Proteasome System ◽

Human Diseases ◽

Intracellular Protein ◽

Nobel Lecture ◽

Intracellular Protein Degradation ◽

Ubiquitin Proteasome

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Gfi1 ubiquitination and proteasomal degradation is inhibited by the ubiquitin ligase Triad1

Blood ◽

10.1182/blood-2006-11-058602 ◽

2007 ◽

Vol 110 (9) ◽

pp. 3128-3135 ◽

Cited By ~ 22

Author(s):

Jurgen A. F. Marteijn ◽

Laurens T. van der Meer ◽

Liesbeth van Emst ◽

Simon van Reijmersdal ◽

Willemijn Wissink ◽

...

Keyword(s):

Cell Proliferation ◽

Ubiquitin Ligase ◽

Ubiquitin Proteasome System ◽

Proteasomal Degradation ◽

Binding Domain ◽

U937 Cells ◽

Dna Binding Domain ◽

Protein Levels ◽

Ubiquitin Ligase Activity ◽

Ubiquitin Proteasome

Abstract Growth factor independence 1 (Gfi1) is a transcriptional repressor essential for the function and development of many different hematopoietic lineages. The Gfi1 protein expression is regulated by the ubiquitin-proteasome system. In granulocytes, Gfi1 is rapidly degraded by the proteasome, while it is more stable in monocytes. How the ubiquitination and degradation of Gfi1 is regulated is unclear. Here, we show that the ubiquitin ligase Triad1 interacts with the DNA-binding domain of Gfi1. Unexpectedly, we found that Triad1 inhibited Gfi1 ubiquitination, resulting in a prolonged half-life. Down-regulation of endogenous Triad1 by siRNAs resulted in increased Gfi1 ubiquitination. In U937 cells, Triad1 caused an increase in endogenous Gfi1 protein levels and slowed cell proliferation in a similar manner when Gfi1 itself was expressed. A Triad1 mutant that lacks the Gfi1-binding domain did not affect Gfi1 levels and proliferation. Because neither proteasome-ubiquitin nor Triad1 ubiquitin ligase activity was required for the inhibition of Gfi1 ubiquitination, these data suggest that Triad1 competes for Gfi1 binding with as yet to be identified E3 ubiquitin ligases that do mark Gfi1 for proteasomal degradation. The finetuning of Gfi1 protein levels regulated by Triad1 defines an unexpected role for this protein in hematopoiesis.

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Intracellular Protein Degradation: From a Vague Idea, through the Lysosome and the Ubiquitin-Proteasome System, and onto Human Diseases and Drug Targeting (Nobel Lecture)

Angewandte Chemie International Edition ◽

10.1002/anie.200501428 ◽

2005 ◽

Vol 44 (37) ◽

pp. 5944-5967 ◽

Cited By ~ 113

Author(s):

Aaron Ciechanover

Keyword(s):

Protein Degradation ◽

Drug Targeting ◽

Ubiquitin Proteasome System ◽

Human Diseases ◽

Intracellular Protein ◽

Nobel Lecture ◽

Intracellular Protein Degradation ◽

Ubiquitin Proteasome

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Patented small molecule inhibitors in the ubiquitin proteasome system

BMC Biochemistry ◽

10.1186/1471-2091-8-s1-s14 ◽

2007 ◽

Vol 8 (Suppl 1) ◽

pp. S14 ◽

Cited By ~ 50

Author(s):

Philippe Guédat ◽

Frédéric Colland

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitors ◽

Ubiquitin Proteasome System ◽

Ubiquitin Proteasome

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Involvement of the Ubiquitin-Proteasome System in the Formation of Experimental Postsurgical Peritoneal Adhesions

Mediators of Inflammation ◽

10.1155/2012/194723 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Clara Di Filippo ◽

Pasquale Petronella ◽

Fulvio Freda ◽

Marco Scorzelli ◽

Marco Ferretti ◽

...

Keyword(s):

Protein Degradation ◽

Ubiquitin Proteasome System ◽

20S Proteasome ◽

Intracellular Protein ◽

Peritoneal Adhesions ◽

Proteasome Subunit ◽

Peritoneal Tissue ◽

Intracellular Protein Degradation ◽

Ubiquitin Proteasome

We investigated the Ubiquitin-Proteasome System (UPS), major nonlysosomal intracellular protein degradation system, in the genesis of experimental postsurgical peritoneal adhesions. We assayed the levels of UPS within the adhered tissue along with the development of peritoneal adhesions and used the specific UPS inhibitor bortezomib in order to assess the effect of the UPS blockade on the peritoneal adhesions. We found a number of severe postsurgical peritoneal adhesions at day 5 after surgery increasing until day 10. In the adhered tissue an increased values of ubiquitin and the 20S proteasome subunit, NFkB, IL-6, TNF-αand decreased values of IkB-beta were found. In contrast, bortezomib-treated rats showed a decreased number of peritoneal adhesions, decreased values of ubiquitin and the 20S proteasome, NFkB, IL-6, TNF-α, and increased levels of IkB-beta in the adhered peritoneal tissue. The UPS system, therefore, is primarily involved in the formation of post-surgical peritoneal adhesions in rats.

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Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes

Blood ◽

10.1182/blood-2006-02-003590 ◽

2006 ◽

Vol 109 (1) ◽

pp. 100-108 ◽

Cited By ~ 14

Author(s):

Jurgen A. F. Marteijn ◽

Laurens T. van der Meer ◽

Liesbeth Van Emst ◽

Theo de Witte ◽

Joop H. Jansen ◽

...

Keyword(s):

Ubiquitin Proteasome System ◽

Proteasomal Degradation ◽

Myeloid Differentiation ◽

Mrna Levels ◽

Monocytic Differentiation ◽

Granulocytic Differentiation ◽

Monocytic Cell ◽

Protein Levels ◽

Ubiquitin Proteasome ◽

Monocytic Lineage

Abstract Gfi1 is a transcriptional repressor essential during myeloid differentiation. Gfi1−/− mice exhibit a block in myeloid differentiation resulting in the accumulation of an immature myelo-monocytic cell population and the complete absence of mature neutrophils. Even though mRNA levels of Gfi1 appear to be very low in monocytes, Gfi1 might play a role in the monocytic lineage as Gfi1−/− mice exhibit diminished monocyte-derived dendritic cells and disturbed cytokine production by macrophages in response to LPS. We show here that Gfi1 protein levels are mainly regulated by the ubiquitin-proteasome system. Upon forced monocytic differentiation of U937 cells, Gfi1 mRNA levels dropped but protein levels increased due to diminished proteasomal turnover. Similarly, Gfi1 mRNA levels are low in primary monocytes whereas the protein is clearly detectable. Conversely, Gfi1 mRNA levels are high in granulocytes but the protein is swiftly degraded by the proteasome in these cells. Chromatin immunoprecipitation experiments showed that Gfi1 binds to the promoter of several granulocyte-specific genes in primary monocytes, including C/EBPα, neutrophil elastase, and Gfi1 itself. The binding of the repressor Gfi1 to these promoters correlated with low expression of these genes in monocytes compared with granulocytes. Our data fit a model in which Gfi1 protein levels are induced in primary monocytes, due to diminished proteasomal degradation, to repress genes that play a role in granulocytic differentiation.

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Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer

10.26434/chemrxiv.13040723 ◽

2020 ◽

Author(s):

Hidetomo Yokoo ◽

Norihito Shibata ◽

Miyako Naganuma ◽

Kiyonaga Fujii ◽

Takahito Ito ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Small Molecule ◽

Allergic Diseases ◽

Ubiquitin Proteasome System ◽

Novel Agents ◽

Biological Research ◽

Prostaglandin D2 ◽

Prostaglandin D Synthase ◽

Ubiquitin Proteasome

Although hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for treatment of a variety of diseases, including allergic diseases and Duchenne muscular dystrophy, no H-PGDS inhibitors have yet been approved for treatment of these diseases. Therefore, the development of novel agents having other mode of actions to modulate the activity of H-PGDS is required. In this study, a chimeric small molecule that degrades H-PGDS via the ubiquitin-proteasome system, PROTAC(H-PGDS)-1, was developed. PROTAC(H-PGDS)-1 is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon). PROTAC(H-PGDS)-1 showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D2 (PGD2) production. Notably, PROTAC(H-PGDS)-1 was slightly more effective in the suppression of PGD2 production than the known inhibitor, TFC-007. Thus, the H-PGDS degrader—PROTAC(H-PGDS)-1—is expected to be useful in biological research and clinical therapies.

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