Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormal survival of retinal pigment epithelium (RPE) cells contributes to the pathogenesis of proliferative vitreoretinopathy (PVR), a sight-threatening disease. In this study, we explored the effect of the anti-rheumatic agent auranofin (AF) on RPE cell survival and studied the underlying signaling mechanisms in vitro. Our results showed that AF inhibited ARPE-19 cell survival in a dose and time-dependent manner. Application of AF induced several effects: a significant decrease in total epidermal growth factor receptor (EGFR) and an increase in phosphorylated EGFR and mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinase (ERK), P38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), c-Jun, mitogen activated protein kinase activated protein kinase 2(MAPKAPK2), and heat shock protein 27 (HSP27). AF also inhibited epidermal growth factor (EGF)-dependent cell proliferation and migration through affecting EGFR/MAPK signaling. The antioxidant N-acetylcysteine (NAC) blocked the AF-induced increase of reactive oxygen species (ROS) production, the reduction of total EGFR, and the phosphorylation of multiple nodes in EGFR/MAPK signaling pathway. P38MAPK inhibitor SB203580, but not inhibitors of EGFR (erlotinib), ERK (FR180204) and JNK (SP600125), suppressed AF-induced phosphorylation of EGFR/p38MAPK/MAPKAPK2/Hsp27. In conclusion, the ROS-dependent phosphorylation of EGFR/MAPK is an important signaling pathway for AF-induced inhibition of RPE cell survival, and AF may have the potential for treatment of abnormal survival of RPE cells in PVR.
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PMID:Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway. 2822 66

Abnormal proliferation and motility of retinal pigment epithelial cells leads to proliferative vitreoretinopathy (PVR). Melatonin is a known effective antitumour and anti-invasive agent, but whether it affects the formation and underlying mechanisms of PVR remains unclear. In this study, the results of the MTT assay, colony formation and propidium iodide (PI) staining with flow cytometry revealed that melatonin dose dependently inhibited epidermal growth factor (EGF)-induced proliferation of human ARPE-19 cells. Furthermore, melatonin reduced EGF-induced motility by suppressing cathepsin S (CTSS) expression. Pretreatment with ZFL (a CTSS inhibitor) or overexpression of CTSS (pCMV-CTSS) significantly inhibited EGF-induced cell motility when combined with melatonin. Epidermal growth factor induced the phosphorylation of AKT(S473)/mTOR (S2448) and transcription factor (c-Jun/Sp1) signaling pathways. Pretreatment of LY294002 (a PI3K inhibitor) or rapamycin (an mTOR inhibitor) markedly reduced EGF-induced motility and p-AKT/p-mTOR/c-Jun/Sp1 expression when combined with melatonin. Taken together, these data indicate that melatonin inhibited EGF-induced proliferation and motility of human ARPE-19 cells by activating the AKT/mTOR pathway, which is dependent on CTSS modulation of c-Jun/Sp1 signalling. Melatonin may be a promising therapeutic drug against PVR.
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PMID:Melatonin attenuates epidermal growth factor-induced cathepsin S expression in ARPE-19 cells: Implications for proliferative vitreoretinopathy. 3160 30