Characterization of Arginylation Branch of N-end Rule Pathway in G-protein-mediated Proliferation and Signaling of Cardiomyocytes

Lee, Minjae; Kim, Dong-Eun; Zakrzewska, Adriana; Yoo, Youngdong; Kim, Su Hyeon; Kim, Sung Tae; Seo, Jai Wha; Lee, Young Sook; Dorn, Gerald W.; Oh, U. T.; Kim, Bo Yeon; Kwon, Yongtae

doi:10.1074/jbc.m112.364117

Cited by 46 publications

(41 citation statements)

References 46 publications

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“…Interestingly, infusion of an RGS4 peptide lacking the aminoterminus (RGS4DN) reversed the attenuated M 4 response of reserpine-treated neurons, suggesting that RGS4DN acted as a dominant negative inhibitor of endogenous RGS4. RGS4 knockout mice confirmed these results and imply a role for RGS4 in the control in motor symptoms of PD associated with increased striatal acetylcholine levels (Chen et al, 2012;Guasch et al, 2013;Jaba et al, 2013;Lee et al, 2012b;Mighiu and Heximer, 2012;Ruiz de Azua et al, 2012b;Stratinaki et al, 2013;Wydeven et al, 2014).…”

Section: Rgs4supporting

confidence: 78%

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

Woodard

Jardín

Berna‐Erro

et al. 2015

International Review of Cell and Molecular Biology

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Section: Rgs4supporting

confidence: 78%

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

Woodard

Jardín

Berna‐Erro

et al. 2015

International Review of Cell and Molecular Biology

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“…The studies have demonstrated that the N-end rule pathway has a strikingly diverse range of developmental and physiological roles, which include the regulation of chromosomal stability [14], spermatogenesis [15], oxygen sensing [16, 19], cardiovascular development [18], muscle wasting [20–23], proteotoxic protein clearance [25], hypertension [26], autophagy [27], neural tube formation [50], bacterial/viral virulence [52, 53], apoptosis [54], and mitophagy [55]. Mutational inactivation of both copies of the UBR1 gene causes Johanson-Blizzard syndrome (JBS), which involves exocrine pancreatic insufficiency and inflammation, physical malformations, and frequent mental retardation [56].…”

Section: Physiological Implications Of the Mammalian N-end Rule Pathwaymentioning

confidence: 99%

Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications

Lee

Jiang

Kwon

et al. 2015

Trends in Pharmacological Sciences

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The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of short-lived substrates determine their metabolic half-lives. Substrates of this pathway have been implicated in the pathogenesis of many diseases, including malignancies, neurodegeneration, and cardiovascular disorders. This review provides a comprehensive overview of current knowledge about the mechanism and functions of the N-end rule pathway. Pharmacological strategies for the modulation of target substrate degradation are also reviewed, with emphasis on their in vivo implications. Given the rapid advances in structural and biochemical understanding of the recognition components (N-recognins) of the N-end rule pathway, small-molecule inhibitors and activating ligands of N-recognins emerge as therapeutic agents with novel mechanisms of action.

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“…Primary MEFs were isolated from mouse embryos approximately on embryonic day (E) 13.5: before the embryonic death from USP14 inactivation [22, 23]. Briefly, embryonic bodies at E13.5 were minced in the presence of trypsin after removal of the head, liver, internal blood clot, and guts.…”

Section: Methodsmentioning

confidence: 99%

Inactivation of USP14 Perturbs Ubiquitin Homeostasis and Delays the Cell Cycle in Mouse Embryonic Fibroblasts and in Fruit Fly Drosophila

Lee

Park

Yun

et al. 2018

Cell Physiol Biochem

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Background/Aims: The 26S proteasome is the key proteolytic complex for recognition and degradation of polyubiquitinated target substrates in eukaryotes. Among numerous proteasome-associated proteins, a deubiquitinating enzyme (DUB) USP14 has been identified as an endogenous inhibitor of the proteasome. Here, we explored the complex regulatory functions of USP14 that involve ubiquitin (Ub) homeostasis and substrate degradation in flies and mammals. Methods: USP14-null primary and immortalized mouse embryonic fibroblasts (MEFs) and USP14 knocked-down Drosophila were analyzed in this study. We measured proteasome and DUB activities using fluorogenic reporter substrates and adduct-forming probes. To examine the levels of ubiquitin, we performed immunoblotting and immunohistochemistry. Mass spectrometry (MS) was used to examine polyUb chain linkages and USP14-interacing proteins. Cell cycle was analyzed by flow cytometry, BrdU labeling, and phospho-histone H3 staining. Results: The homeostasis of Ub in USP14^–/–MEFs was markedly perturbed because of facilitated clearance of Ub. This phenomenon was recapitulated in muscles of USP14-deficient Drosophila with old ages. Absolute quantitation using MS also revealed that USP14^–/– MEFs contained significantly increased amounts of Ub, compared with wild-type. The key phenotype of USP14^–/– MEFs was their delayed proliferation originated from prolonged interphase possibly through aberrant degradation of cyclins A and B1. We found that knocking down USP14 in Drosophila resulted in delayed eye development associated with reduced mitotic activity. Conclusion: Our study identifies novel cellular functions of USP14 not only in cellular Ub hometostasis but also in cell cycle progression. USP14 was also essential for proper Drosophila eye development. These results strongly suggest that the USP14-mediated proteasome activity regulation may be directly related to various human diseases including cancer.

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Characterization of Arginylation Branch of N-end Rule Pathway in G-protein-mediated Proliferation and Signaling of Cardiomyocytes

Cited by 46 publications

References 46 publications

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications

Inactivation of USP14 Perturbs Ubiquitin Homeostasis and Delays the Cell Cycle in Mouse Embryonic Fibroblasts and in Fruit Fly Drosophila

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