Translocation of PKC-betaII is mediated via RACK-1 in the neuronal cells following dioxin exposure.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to induce neurotoxic effects. However, the mechanism of TCDD-mediated signaling pathways and its possible molecular targets in neurons remains unknown. In this study, we analyzed effects of TCDD on neurofilament subunits, receptor for activated C kinase-1 (RACK-1), and PKC-betaII activity in developing neuronal cells. TCDD induced a significant increase of RACK-1, an adaptor protein for protein kinase C (PKC), in cerebellar granule cells in both dose- and time-dependent manner, indicating that RACK-1 is a sensitive molecular target in neuronal cells for TCDD exposure. TCDD induced a dose-dependent translocation of PKC-betaII from cytosol to membrane fractions. However, when RACK-1 induction was blocked by antisense oligonucleotide or alpha-naphthoflavone, Ah receptor (AhR) inhibitor, the translocation of PKC-betaII was inhibited. Our data suggests that TCDD activates PKC-betaII via RACK-1 in an AhR-dependent manner. This is the first report identifying RACK-1 as a target molecule involved in TCDD-mediated signaling pathways. TCDD exposure also increased the level of neurofilament-H mRNA. These results suggest that identification of target molecules may contribute to improve our understanding of TCDD-mediated signaling pathway and the risk assessment of TCDD-induced neurotoxicities.
Lee
Hyun-Gyo
HG
Department of Pharmacology and Toxicology, School of Medicine, Catholic University of Daegu, 3056-6 Daemyong-4-dong, Namgu, Daegu 705-718, Republic of Korea.
Kim
Sun-Young
SY
Choi
Eun-Jung
EJ
Park
Ki-Yeon
KY
Yang
Jae-Ho
JH
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000737:chemistry* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000075370:Receptors for Activated C Kinase; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D001571:Benzoflavones; D004785:Environmental Pollutants; D016900:Neurofilament Proteins; D016376:Oligonucleotides, Antisense; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D000075370:Receptors for Activated C Kinase; D018336:Receptors, Aryl Hydrocarbon; D011956:Receptors, Cell Surface; C051774:neurofilament protein H; C011512:alpha-naphthoflavone; D011493:Protein Kinase C; D064546:Protein Kinase C beta