Controlling Nuclear NF-κB Dynamics by β-TrCP—Insights from a Computational Model

Benary, Uwe; Wolf, Jana

doi:10.3390/biomedicines7020040

Cited by 11 publications

(11 citation statements)

References 89 publications

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“…401 β-TrCP1 can ubiquitinate the phosphorylated inhibitor of nuclear factor-κB (IκB) and lead to its degradation by the proteasomal pathway. 402,403 A small phosphopeptide agonist has been designed to target the IκB Ub ligase, and this peptide can inhibit IκB degradation in TNF-stimulated HeLa cells. 404 Erioflorin, an inhibitor of β-TrCP1, has been shown to suppress the activity of NF-κB and decelerate cell proliferation in various cancer cells by stabilizing the tumor suppressor PDCD4 (Fig.…”

Section: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

375

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

375

308

View full text Add to dashboard Cite

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“…Many other molecules have reduced SKP2 expression in cancer cells, including SZL-P1-41 [ 154 ], longikaurin A [ 155 ], curcumin [ 156 , 157 ], and other natural compounds [ 156 , 210 , 211 , 212 , 213 ]. SCF- β -TrCP1 can induce proteasomal degradation of the inhibitor of nuclear factor-

B (I

B) via ubiquitination, resulting in overexpression of NF-

B signaling and tumorigenesis [ 214 , 215 , 216 ]. Inhibition of β -TrCP1 has been achieved by erioflorin, resulting in stabilization of tumor suppressor genes and decreased cancer cell proliferation [ 161 ].…”

Section: Small-molecule Inhibitors Targeting the Upsmentioning

confidence: 99%

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

LaPlante

Zhang

2021

Cancers

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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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“…The NF-κB modulates a diverse spectrum of biological processes and operates as a central regulator of inflammation ( Tian et al., 2005 ; Wang et al., 2017 ). The NF-κB signaling cascade has been well studied in IBD treatment and is often dysregulated in patients, resulting in aberrant cytokine and chemokine production in the gut ( Zaidi and Wine, 2018 ; Benary and Wolf, 2019 ). Inflammation and carcinogenesis have been associated with NF-κB signaling ( Huang et al., 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Bilobalide Alleviated Dextran Sulfate Sodium-Induced Experimental Colitis by Inhibiting M1 Macrophage Polarization Through the NF-κB Signaling Pathway

et al. 2020

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Bilobalide, a unique Ginkgo biloba constituent has attracted significant interest as a novel therapeutic option for neuronal protection. However, there is paucity of data on its effect on colitis. This work sought to evaluate the effect of bilobalide on macrophage polarization in vitro and dextran sulfate sodium (DSS) induced colitis in vivo. Through the 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and annexin V/PI assay, it was shown that bilobalide has no significant toxicity on macrophage. Lipopolysaccharide (LPS) and interferon-gamma (IFN-g) induced macrophage activation and polarization were significantly suppressed by bilobalide as indicated by reduced expression of cytokine, major histocompatibility complex II (MHC-II), and CD11c. Pertinently, the signaling pathway study showed that the phosphorylation of p65 and its nuclear translocation were decreased while STAT1 was not affected. In DSS-treated mice, administration (i.g) of three doses of bilobalide na\mely 1.25 mg/kg (low dose group), 2.5 mg/kg (medium dose group), and 5 mg/kg (high dose group) was performed daily starting from day 1 to day 10. Medium and high dose bilobalide markedly reduced the inflammation of colitis proved via elevation of bodyweight, decrement in disease activity index (DAI), alleviation of colon damage as well as reduction in activity of colon tissue myeloperoxidase activity. In accordance with the in vitro results, the levels of inflammatory cytokines such as interleukin 6 (IL-6), IL-1b, and tumor necrosis factor (TNF-a) in serum as well as messenger RNA (mRNA) expression in colon were obviously reduced in the bilobalide treated groups. Also, factor nuclear factor kappa B (NF-kB) signaling pathway was decreased significantly by bilobalide treatment. Collectively, these results indicated that administration of bilobalide improved experimental colitis via inhibition of M1 macrophage polarization through the NF-kB signaling pathway. Thus, bilobalide could act as a potential drug for the treatment of inflammatory bowel disease (IBD) in the not-too-distant future.

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Controlling Nuclear NF-κB Dynamics by β-TrCP—Insights from a Computational Model

Cited by 11 publications

References 89 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

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

Bilobalide Alleviated Dextran Sulfate Sodium-Induced Experimental Colitis by Inhibiting M1 Macrophage Polarization Through the NF-κB Signaling Pathway

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