Cyclin G2 regulates canonical Wnt signalling via interaction with Dapper1 to attenuate tubulointerstitial fibrosis in diabetic nephropathy

Zhao, Chenyang; Gao, Jinlan; Li, Sen; Liu, Qi; Hou, Xiaoyu; Xing, Xuesha; Wang, Danning; Sun, Manni; Wang, Shusen; Luo, Yang

doi:10.1111/jcmm.14946

Cited by 12 publications

(12 citation statements)

References 53 publications

(119 reference statements)

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“…It has been shown that carnosine could down-regulate COL-I, α-SMA and fibronectin. The main manifestations of renal fibrosis include exudation of inflammatory cells, activation and proliferation of fibroblasts, mass production of extracellular matrix, loss of renal intrinsic cells and reduction of microvessels [ 17 , 18 ]. It is important to note that the inflammatory response runs through the entire process of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis

et al. 2020

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Diabetic nephropathy (DN) is a common microvascular complication of diabetes and the main cause of end-stage nephropathy (ESRD). Inflammation and fibrosis play key roles in the development and progression of diabetic nephropathy. By using in vivo and in vitro DN models, our laboratory has identified the protective role of carnosine (CAR) on renal tubules. Our results showed that carnosine restored the onset and clinical symptoms as well as renal tubular injury in DN. Furthermore, carnosine decreased kidney inflammation and fibrosis in DN mice. These results were consistent with high glucose (HG)-treated mice tubular epithelial cells (MTECs). Using web-prediction algorithms, cellular thermal shift assay (CETSA) and molecular docking, we identified glycine N-methyltransferase (GNMT) as a carnosine target. Importantly, we found that GNMT, a multiple functional protein that regulates the cellular pool of methyl groups by controlling the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), was down-regulated significantly in the serum of Type 1 DM patients and renal tissues of DN mice. Moreover, using cultured TECs, we confirmed that the increased GNMT expression by transient transfection mimicked the protective role of carnosine in reducing inflammation and fibrosis. Conversely, the inhibition of GNMT expression abolished the protective effects of carnosine. In conclusion, carnosine might serve as a promising therapeutic agent for DN and GNMT might be a potential therapeutic target for DN.

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Section: Discussionmentioning

confidence: 99%

Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis

et al. 2020

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“…Because it is a link between growth signaling and cell division, cyclin D1 is a downstream target of several mitotic signals, such as AKT [ 45 ], ERK [ 46 ], NF-κB [ 47 ], and Wnt/β-catenin [ 48 ]. In addition to studying the relationship between CCNG2 and the Wnt/β-catenin signaling pathway [ 28 , 30 ], further research is required to determine whether other signaling pathways participate in the cyclin D1 abnormality mediated by CCNG2 during placental development.…”

Section: Discussionmentioning

confidence: 99%

“…CCNG2 has been shown to inhibit gastric cancer cell growth and migration by suppressing Wnt/β-catenin signaling [ 28 ]; to repress glycolysis by interacting with lactate dehydrogenase A (LDHA) [ 29 ]; and to inhibit glioma tumor progression [ 29 ]. Moreover, CCNG2 was found to bind to Dapper1 and protect against renal injury and fibrosis in diabetic nephropathy by suppressing Wnt/β-catenin signaling [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclin G2 Is Involved in the Proliferation of Placental Trophoblast Cells and Their Interactions with Endothelial Cells

et al. 2020

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Background Remodeling of maternal spiral arteries after embryo implantation relies on well-regulated trophoblast functions. Although cyclin G2 (CCNG2) is thought to be involved in placental development and function, its role in trophoblasts and the mechanisms underlying placental development and function remain unclear. The present study investigated the potential role of CCNG2 in trophoblast cell proliferation and their interactions with endothelial cells. Material/Methods CCNG2 levels were modified by stable infection of HTR8/SVneo cells with lentiviruses overexpressing and silencing CCNG2. Cell proliferation was measured using CCK-8 assays. Network formation assays were performed using trophoblasts alone and co-cultured trophoblasts and endothelial cells to measure angiogenesis of trophoblasts and trophoblast-endothelial interactions. Levels of angiogenic factors (VEGF and sFlt-1) in the supernatant were measured by ELISA, and the expression of cell cycle regulatory (cyclin D1) and invasive (MMP2, MMP3, MMP9) markers implicated in artery remodeling were measured by western blotting. Results Ectopic expression of CCNG2 blocked the proliferation of HTR8/SVneo cells, as well as their abilities to form networks and integrate into human umbilical vein endothelial cells, whereas CCNG2 inhibition had the opposite effects. CCNG2 upregulation significantly reduced the expression of VEGF, cyclin D1, MMP2, MMP3, and MMP9, but enhanced the expression of sFlt-1. In contrast, CCNG2 downregulation had the opposite effects. Conclusions CCNG2 plays a critical role in trophoblast proliferation and trophoblast-endothelial cell interactions by significant affecting cell cycle, angiogenic, and invasive markers. CCNG2 may thus be a novel marker for the treatment of placental disorders.

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“…Anticancer drugs have also been shown to increase the level of cyclin G2 to induce arrest, knockdown of cyclin G2 reduces the potency of cotylenin A and rapamycin (14). The precise mechanism of action of cyclin G2 has not been elucidated there are reports that speculate on the mechanisms by which cyclin G2 is expressed (15). However, the exact role that cyclin G2 plays in OSCC and other cancers is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Cyclin G2 Inhibits Oral Squamous Cell Carcinoma Growth and Metastasis by Binding to IGFBP3 and Regulating the FAK-SRC-STAT Signaling Pathway

et al. 2020

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The cell cycle protein cyclin G2 is considered a tumor suppressor. However, its regulatory effects and potential mechanisms in oral cancers are not well understood. This study aimed to investigate the effect of cyclin G2 on oral squamous cell carcinoma (OSCC). The data from 80 patients with OSCC were utilized to predict the abnormal expression of cyclin G2. The proliferation and metastasis were determined by a cell counting Kit-8 assay, flow cytometry, a wound-healing assay, and a cell invasion assay. The expression of key proteins and genes associated with the cyclin G2 signaling pathways was determined by western blotting and real-time PCR, respectively. The orthotopic nude mice model was established by a mouth injection of SCC9 cells overexpressing cyclin G2. We showed that the low level of cyclin G2 in OSCC, which is negatively correlated with clinical staging, was a negative prognostic factor for the disease. We also found that cyclin G2 inhibited the proliferation, metastasis, and blocked the cell cycle at G1/S of OSCC cells, suggesting that cyclin G2 has an inhibitory effect in OSCC. Mechanistically, cyclin G2 inhibited the growth and metastasis of OSCC by binding to insulin-like growth factor binding protein 3 (IGFBP3) and regulating the focal adhesion kinase (FAK)-SRC-STAT signal transduction pathway. Cyclin G2 competed with integrin to bind to IGFBP3; the binding between integrin and IGFBP3 was reduced after cyclin G2 overexpression, thereby inhibiting the phosphorylation of FAK and SRC. These results showed that cyclin G2 inhibited the progression of OSCC by interacting with IGFBP3 and that it may be a new target for OSCC treatment.

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Cyclin G2 regulates canonical Wnt signalling via interaction with Dapper1 to attenuate tubulointerstitial fibrosis in diabetic nephropathy

Cited by 12 publications

References 53 publications

Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis

Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis

Cyclin G2 Is Involved in the Proliferation of Placental Trophoblast Cells and Their Interactions with Endothelial Cells

Cyclin G2 Inhibits Oral Squamous Cell Carcinoma Growth and Metastasis by Binding to IGFBP3 and Regulating the FAK-SRC-STAT Signaling Pathway

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