SP600125 Inhibits Cap-dependent Translation Independently of the c-Jun N-terminal Kinase Pathway

Ito, Masako; Kitamura, Hiroshi; Kikuguchi, Chisato; Hase, Koji; Ohno, Hiroshi; Ohara, Osamu

doi:10.1247/csf.10025

Cited by 5 publications

(3 citation statements)

References 23 publications

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“…A previous study suggested that inhibition of JNK results in the enhancement of TGF-β1-activated Smad2 signaling [29]. Therefore, the above phenomenon could be explained as follows: with the inhibition of the JNK pathway alone, enhanced virus binding caused by the TGF-β1-activated Smad2 signaling still occurred, but the internalization and/or transcription/replication of the virus were completely suppressed as the overall protein synthesis was repressed as a result of the inhibited JNK signaling [30].…”

Section: Discussionmentioning

confidence: 98%

The Epithelial-to-Mesenchymal Transition-Like Process Induced by TGF-β1 Enhances Rubella Virus Binding and Infection in A549 Cells via the Smad Pathway

et al. 2021

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Virus–host cell interactions in rubella virus (RuV) are of great interest in current research in the field, as their mechanism is not yet well understood. By hypothesizing that the epithelial-to-mesenchymal transition (EMT) may play a role in RuV infection, this study aimed to investigate the influence of TGF-β1-induced EMT of human lung epithelial A549 cells on the infectivity of RuV. A549 cells were cultured and treated with TGF-β1 for 1 to 2 days prior to virus infection (with a clinical strain). Viral infectivity was determined by flow cytometry analysis of cells harvested at 24 and 48 h post-infection (hpi) and by titration of supernatants collected at 48 hpi. The results showed that the percentages of the TGF-β1-treated A549 cells that were positive for RuV were at least twofold higher than those of the control, and the viral progeny titers in the supernatants collected at 48 hpi were significantly higher in the treatment group than in the control group. In addition, the virus binding assay showed a strong increase (more than threefold) in the percentages of RuV-positive cells, as determined by flow cytometry analysis and further confirmed by real-time PCR. Such an enhancement effect on RuV infectivity was abolished using LY364947 or SB431542, inhibitors of the TGF-β/Smad signaling pathway. The findings suggest that the TGF-β1-induced EMT-like process enhances RuV binding and infection in A549 cells via the Smad pathway. Further studies are necessary to identify possible proteins that facilitate viral binding and entry into treated cells.

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Section: Discussionmentioning

confidence: 98%

The Epithelial-to-Mesenchymal Transition-Like Process Induced by TGF-β1 Enhances Rubella Virus Binding and Infection in A549 Cells via the Smad Pathway

et al. 2021

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“…Most USP inhibitors have been validated for their specificity using a limited number of USP species [ 33 ]. Considering that even common inhibitors have unexpected effects on different enzymes [ 240 , 241 ], gathering information about the specificity of USP inhibitors is desirable.…”

Section: Perspectivesmentioning

confidence: 99%

Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

Kitamura

2023

IJMS

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Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, and enzymatic activity. Ubiquitin-specific proteases (USPs) constitute the largest deubiquitinating enzyme family. To date, accumulating evidence indicates that several USPs positively and negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 in adipose tissue macrophages, USP9X, 20, and 33 in myocytes, USP4, 7, 10, and 18 in hepatocytes, and USP2 in hypothalamus improve hyperglycemia, whereas USP19 in adipocytes, USP21 in myocytes, and USP2, 14, and 20 in hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 14, 15, 22, 36, and 48 modulate the progression of diabetic nephropathy, neuropathy, and/or retinopathy. USP4, 10, and 18 in hepatocytes ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic USP2, 11, 14, 19, and 20 exacerbate it. The roles of USP7 and 22 in hepatic disorders are controversial. USP9X, 14, 17, and 20 in vascular cells are postulated to be determinants of atherosclerosis. Moreover, mutations in the Usp8 and Usp48 loci in pituitary tumors cause Cushing syndrome. This review summarizes the current knowledge about the modulatory roles of USPs in energy metabolic disorders.

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“…From this perspective, further studies using Usp2KO mice or specific USP2 inhibitors may be useful for the functional validation of the roles of USP2 in vivo. Meanwhile, drug specificity should be taken into consideration, because many chemical inhibitors have unexpected molecular targets [159]; for example, a recent paper reported that a USP2 blocker also inhibits severe acute respiratory syndrome coronavirus 2 papain-like protease [160]. Considering that these inhibitors can affect enzymes with similar structures, chemical inhibitors of USP2 could perturb other endogenous proteins.…”

Section: Perspectivesmentioning

confidence: 99%

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

Kitamura

Hashimoto

2021

IJMS

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Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.

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SP600125 Inhibits Cap-dependent Translation Independently of the c-Jun N-terminal Kinase Pathway

Cited by 5 publications

References 23 publications

The Epithelial-to-Mesenchymal Transition-Like Process Induced by TGF-β1 Enhances Rubella Virus Binding and Infection in A549 Cells via the Smad Pathway

The Epithelial-to-Mesenchymal Transition-Like Process Induced by TGF-β1 Enhances Rubella Virus Binding and Infection in A549 Cells via the Smad Pathway

Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

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