The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges

Tundo, Grazia R.; Sbardella, Diego; Santoro, Anna Maria; Coletta, Andrea; Oddone, Francesco; Grasso, Giuseppe; Milardi, Danilo; Lacal, Pedro Miguel; Marini, Stefano; Purrello, Roberto; Graziani, Grazia; Coletta, Massimo

doi:10.1016/j.pharmthera.2020.107579

Cited by 69 publications

(94 citation statements)

References 1,108 publications

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“…For instance, proteasome inhibitors have been clinically used in the treatment of multiple myeloma (MM) (Tundo et al, 2020). Previous studies have demonstrated that the dysregulation of NF-κB pathway contribute to the development and clinical manifestations of MM via NF-κB target genes, including the growth factor interleukin-6 and insulin-like growth factor-1, cell cycle regulators cyclin D and c-Myc, and pro-angiogensis factors vascular endothelial growth factor-C and placental growth factor (Vrábel et al, 2019).…”

Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

“…Previous studies have demonstrated that the dysregulation of NF-κB pathway contribute to the development and clinical manifestations of MM via NF-κB target genes, including the growth factor interleukin-6 and insulin-like growth factor-1, cell cycle regulators cyclin D and c-Myc, and pro-angiogensis factors vascular endothelial growth factor-C and placental growth factor (Vrábel et al, 2019). Because the ubiquitination and subsequent degradation of IκBα in the proteasome are predominant mechanisms of the NF-κB pathway activation (Feng et al, 2017;Tundo et al, 2020), bortezomib, a reversible proteasome inhibitor, was used in the treatment of MM. Bortezomib binds directly to the β5-subunit of the proteasome and inhibits the enzymatic activity of the proteasome complex.…”

Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

“…Compared with bortezomib, ixazomib inhibited tumor proteasome activity for a longer duration and exhibited greater antitumor effect in OCI-Ly10 and PHTX22L lymphoma mouse models (Narayanan et al, 2020). In addition to carfilzomib and ixazomib, second-generation proteasome inhibitors include oprzomib, dilanzomib and malizomib, and their clinical trials are underway (Tundo et al, 2020).…”

Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

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Post-translational Modifications of IκBα: The State of the Art

Wang

Peng

Huang

et al. 2020

Front. Cell Dev. Biol.

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The nuclear factor-kappa B (NF-κB) signaling pathway regulates a variety of biological functions in the body, and its abnormal activation contributes to the pathogenesis of many diseases, such as cardiovascular and respiratory diseases and cancers. Therefore, to ensure physiological homeostasis of body systems, this pathway is strictly regulated by IκBα transcription, IκBα synthesis, and the IκBα-dependent nuclear transport of NF-κB. Particularly, the post-translational modifications of IκBα including phosphorylation, ubiquitination, SUMOylation, glutathionylation and hydroxylation are crucial in the abovementioned regulatory process. Because of the importance of the NF-κB pathway in maintaining body homeostasis, understanding the post-translational modifications of IκBα can not only provide deeper insights into the regulation of NF-κB pathway but also contribute to the development of new drug targets and biomarkers for the diseases.

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Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

See 1 more Smart Citation

Post-translational Modifications of IκBα: The State of the Art

Wang

Peng

Huang

et al. 2020

Front. Cell Dev. Biol.

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“…This system involves the covalent attachment of poly-UB chains to target proteins. Tagging of lamina-associated proteins with UB is an important modification for protein turnover [132,133]. An alternative to autophagy is ubiquitin-dependent degradation of proteins by the 26S proteasome system.…”

Section: Mechanisms Marking Proteins For Removal From the Laminamentioning

confidence: 99%

The Nuclear Lamina: Protein Accumulation and Disease

et al. 2020

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Cellular health is reliant on proteostasis—the maintenance of protein levels regulated through multiple pathways modulating protein synthesis, degradation and clearance. Loss of proteostasis results in serious disease and is associated with aging. One proteinaceous structure underlying the nuclear envelope—the nuclear lamina—coordinates essential processes including DNA repair, genome organization and epigenetic and transcriptional regulation. Loss of proteostasis within the nuclear lamina results in the accumulation of proteins, disrupting these essential functions, either via direct interactions of protein aggregates within the lamina or by altering systems that maintain lamina structure. Here we discuss the links between proteostasis and disease of the nuclear lamina, as well as how manipulating specific proteostatic pathways involved in protein clearance could improve cellular health and prevent/reverse disease.

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“…Alterations to protein degradation have been implicated in a broad spectrum of neurodegenerative conditions including PD, HD, Multiple Sclerosis and ALS (Mitra et al, 2009;Koch et al, 2015;Albert et al, 2017;Mitsui et al, 2018). UPS and autophagy have become increasingly pursued areas of study in conjunction with neurodegenerative and protein aggregation diseases (George et al, 2018;Kabir et al, 2020;Kumar et al, 2020;Lambert-Smith et al, 2020;Lim et al, 2020;Papanikolopoulou and Skoulakis, 2020;Tundo et al, 2020).…”

Section: Protein Degradation and Diseasementioning

confidence: 99%

Homeostatic Roles of the Proteostasis Network in Dendrites

Lottes

Cox

2020

Front. Cell. Neurosci.

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Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived, exhibiting architecturally complex and diverse multipolar projection morphologies that can span great distances. These properties present unique demands on proteostatic machinery to dynamically regulate the neuronal proteome in both space and time. Proteostasis is regulated by a distributed network of cellular processes, the proteostasis network (PN), which ensures precise control of protein synthesis, native conformational folding and maintenance, and protein turnover and degradation, collectively safeguarding proteome integrity both under homeostatic conditions and in the contexts of cellular stress, aging, and disease. Dendrites are equipped with distributed cellular machinery for protein synthesis and turnover, including dendritically trafficked ribosomes, chaperones, and autophagosomes. The PN can be subdivided into an adaptive network of three major functional pathways that synergistically govern protein quality control through the action of (1) protein synthesis machinery; (2) maintenance mechanisms including molecular chaperones involved in protein folding; and (3) degradative pathways (e.g., Ubiquitin-Proteasome System (UPS), endolysosomal pathway, and autophagy. Perturbations in any of the three arms of proteostasis can have dramatic effects on neurons, especially on their dendrites, which require tightly controlled homeostasis for proper development and maintenance. Moreover, the critical importance of the PN as a cell surveillance system against protein dyshomeostasis has been highlighted by extensive work demonstrating that the aggregation and/or failure to clear aggregated proteins figures centrally in many neurological disorders. While these studies demonstrate the relevance of derangements in proteostasis to human neurological disease, here we mainly review recent literature on homeostatic developmental roles the PN machinery plays in the establishment, maintenance, and plasticity of stable and dynamic dendritic arbors. Beyond basic housekeeping functions, we consider roles of PN machinery in protein quality control mechanisms linked to dendritic plasticity (e.g., dendritic spine remodeling during LTP); cell-type specificity; dendritic morphogenesis; and dendritic pruning.

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The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges

Cited by 69 publications

References 1,108 publications

Post-translational Modifications of IκBα: The State of the Art

Post-translational Modifications of IκBα: The State of the Art

The Nuclear Lamina: Protein Accumulation and Disease

Homeostatic Roles of the Proteostasis Network in Dendrites

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