A Novel Target of Mizoribine Inhibiting Mesangial Cell Proliferation: S Phase Kinase-Associated Protein 2

Liu, Shuxin; Xie, Yuansheng; Lv, Yang; Fu-fang, Qin; Fu, Bo; Shu, Shi; Yin, Zhimin; Hong, Quan; Zhang, Xueguang; Wang, Jianzhong; Chen, Ming; Chen, Xiangmei

doi:10.1159/000320334

Cited by 6 publications

(7 citation statements)

References 38 publications

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“…In our study, there were no changes in the mRNA levels of cyclin D1, CDK2, or CDK6 while the proteins expression was significantly reduced after miR-34a transfection; however, the mRNA level of cyclin E was decreased in the miR-34a-transfected RMCs. Moreover, both p27 kip1 protein and mRNA levels were increased in the miR-34a-transfected group, which is consistent with the effect on mesangial cell proliferation [44, 48]. …”

Section: Discussionsupporting

confidence: 77%

miR-34a regulates mesangial cell proliferation via the PDGFR-β/Ras-MAPK signaling pathway

Chen

Liu

Mei

et al. 2014

Cell. Mol. Life Sci.

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The main pathological characteristic of glomerulonephritis is diffuse mesangial cell proliferation. MiR-34a is associated with the proliferation of various organs and cancer cells. However, the role of miR-34a in renal proliferation diseases is not clear. Therefore, this study aimed to elucidate the mechanism of miR-34a in the regulation of renal mesangial cell proliferation. The miR-34a expression level at different time points in an anti-Thy1 mesangial proliferative nephritis rat model was determined by qRT-PCR. The cell proliferation rate and cell cycle changes were measured in the in vitro cultured rat mesangial cells (RMCs). Our results suggested that miR-34a expression was negatively correlated with the degree of cell proliferation in the anti-Thy1 nephritis model. MiR-34a could extend the G0/G1 phase and block cell proliferation in RMCs. Dual-luciferase assay results showed that there were binding sites of miR-34a at 3′-UTR of platelet-derived growth factor receptor-β (PDGFR-β). MiR-34a can inhibit PDGFR-β protein expression at a post-transcriptional level, suppress Ras/MAPK signaling pathways, and down-regulate expression of cell cycle proteins at the G0/G1 phase, such as cyclin D1, CDK4/CDK6. In addition, miR-34a may also inhibit RMC proliferation by directly targeting cyclin E and CDK2. MiR-34a inhibits exogenous stimuli-induced proliferation of mesangial cells. Expression levels of phospho-PDGFR-β and phospho-MEK1 (an important downstream molecule in PDGFR-β-induced signaling pathway) were significantly increased in the anti-Thy-1 nephritis rat model. These results suggest that miR-34a may regulate RMC proliferation by directly inhibiting expressions of PDGFR-β, MEK1, and cell cycle proteins, cyclin E and CDK2.

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Section: Discussionsupporting

confidence: 77%

miR-34a regulates mesangial cell proliferation via the PDGFR-β/Ras-MAPK signaling pathway

Chen

Liu

Mei

et al. 2014

Cell. Mol. Life Sci.

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“…Skp2 deficiency restricts cell development through the up-regulation of p21, p27, and ATF4 [34]. Down-regulation of Skp2 inhibited mesangial cell proliferation [35,36], and Skp2 accumulation causes podocyte injury [37]. However, the role of Skp2 in PTECs is unknown in DN.…”

Section: Discussionmentioning

confidence: 99%

The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy

Tsai

Kuo

et al. 2018

JCM

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Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced β-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels. Transcriptome analysis of PTECs from a type 2 diabetic patient and a normal individual using next generation sequencing (NGS) and systematic bioinformatics analyses indicated that miR-378i and its downstream target S-phase kinase protein 2 (Skp2) contribute to HG-induced senescence in PTECs. High glucose (HG) elevated miR-378i expression in PTECs, and miR-378i transfection reduced Skp2 expression. Urinary miR-378i levels were elevated in both db/db mice and type 2 diabetic patients, whereas decreased Skp2 levels were shown in proximal tubule of db/db mice and human DN. Moreover, urinary miR-378i levels were positively correlated with urinary senescence-associated secretory phenotype cytokines and renal function in in vivo and human study. This study demonstrates that the interaction between miR-378i and Skp2 regulates PTEC senescence of DN. miR-378i has the potential to predict renal injury in DN. These findings suggest future applications in both therapy and in predicting renal dysfunction of DN.

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“…Similarly, some antimetabolites minimally changed ENT1 activity within a 2 SD variation (ribavirin, methotrexate and ganciclovir) in contrast to 5-FU. In addition, the inducers for cell cycle at S phase such as hydroxyurea (21) and mizoribine (22) did not increase ENT1 activity in this system. It is thought that the potency or duration of ENT1 activation by each agent would be different as we used a fixed concentration for screening and obtained various ranges of cytotoxicity (Fig.…”

Section: Discussionmentioning

confidence: 65%

Etoposide increases equilibrative nucleoside transporter 1 activity and fluorothymidine uptake: Screening of 60 cytotoxic agents

Lee

2012

Oncology Reports

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H]FLT uptake accompanying cell cycle arrest at S/G2/M phase and the increase in TK1 expression and activity in both ENT1-low expressing HT29 and ENT1-high expressing MDA-MB-231 cells. The inhibition of ENT1 activity by dipyridamol or S-(p-nitrobenzyl)-6-thioinosine repressed the etoposide-induced cell death in HeLa cells, whereas it induced no changes in the other cell lines. In conclusion, etoposide is identified as a potent inducer for ENT1 activity and [ 3 H]FLT uptake. The role of ENT1 activity by etoposide was cell-type dependent, which requests caution for the application of ENT1-mediated [ 18 F]FLT flare for treatment monitoring.

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A Novel Target of Mizoribine Inhibiting Mesangial Cell Proliferation: S Phase Kinase-Associated Protein 2

Cited by 6 publications

References 38 publications

miR-34a regulates mesangial cell proliferation via the PDGFR-β/Ras-MAPK signaling pathway

miR-34a regulates mesangial cell proliferation via the PDGFR-β/Ras-MAPK signaling pathway

The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy

Etoposide increases equilibrative nucleoside transporter 1 activity and fluorothymidine uptake: Screening of 60 cytotoxic agents

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