title: Transcriptional and translational regulation of COX-2 expression by             cadmium in C6 glioma cells.
abstract: High exposure to cadmium is a risk factor for many neuronal diseases. Overexpression of cyclooxygenase (COX)-2 is linked to many neuroinflammatory and neoplastic diseases. We, herein, investigated the effect of cadmium on the expression of COX-2 in C6 rat glioma cells. Treatment with cadmium sulfate (cadmium) increased the expression of COX-2 mRNA. Remarkably, cadmium treatment further increased expression of not only the N-glycosylated COX-2 protein of 72 kDa but also the unglycosylated COX-2 of 66 kDa, as assessed by the unglycosylated COX-2 induced by tunicamycin or glucosamine, known inhibitors of COX-2 N-glycosylation. Of note, when translation was blocked in the presence of cycloheximide (CHX), levels of both N-glycosylated and unglycosylated COX-2 proteins induced by cadmium rapidly declined but the decline was prevented by MG132, a 26S proteasomal inhibitor. However, in the absence of CHX, cadmium induced and maintained expression of the unglycosylated COX-2 proteins. Pharmacological inhibition studies importantly demonstrated that the cadmium-mediated COX-2 transcriptional upregulation in C6 cells was not shown by exogenous glutathione (GSH) supplementation or treatment with inhibitors of extracellular signal-regulated protein kinase-1/2 (ERK-1/2), p38 MAPK and c-Jun N-terminal protein kinase-1/2 (JNK-1/2), respectively. Expression of COX-2 was not noted in C6 cells exposed to other heavy metals (cobalt or manganese). These results demonstrate that cadmium specifically induces expression of COX-2 through both transcriptional and co-translational (N-glycosylation) regulation in C6 cells in which the cadmium-induced COX-2 transcriptional upregulation is closely related to oxidative stress-dependent activation of the family of MAPKs and the cadmium-induced expression of both N-glycosylated and unglycosylated COX-2 proteins is proteasome- and translation-dependent.
authors: Department of Medical Genetic Engineering, School of Medicine,                     Keimyung University, Dalseo-gu, Daegu 704-701, Republic of Korea.
authors: Yu-Kyoung
authors: YK
authors: Park
authors: Hua
authors: H
authors: Hong
authors: Byeong-Churl
authors: BC
authors: Jang
mesh_terms: D000818:Animals; D002104:Cadmium / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004785:Environmental Pollutants / Q000378:metabolism*; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation; D020935:MAP Kinase Signaling System; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D004785:Environmental Pollutants; D012333:RNA, Messenger; D002104:Cadmium; D051546:Cyclooxygenase 2; D046988:Proteasome Endopeptidase Complex