title: Proteasome inhibitor differentially regulates expression of the major immediate early genes of human cytomegalovirus in human central nervous system-derived cell lines.
abstract: Proteasome inhibitor, which inhibits NF-kappaB activation, has been reported to activate c-Jun N-terminal kinase (JNK)-c-Jun pathway. In this study, we investigated the effects of proteasome inhibitor on the human cytomegalovirus (HCMV) major immediate early (MIE) gene expression in human central nervous system (CNS)-derived cell lines. Treatment of HCMV-infected 118MGC glioma and U373-MG astrocytoma cells with three proteasome inhibitors, MG132, clasto-lactacystin beta-lactone, and epoxomicin, suppressed MIE protein expression. In contrast, in HCMV-infected IMR-32 neuroblastoma cells, the proteasome inhibitors increased MIE protein expression, even in the presence of NF-kappaB inhibitor SN-50. A luciferase reporter assay demonstrated that MG132 markedly elevated the MIE promoter/enhancer (MIEP) activity in IMR-32 cells, but down-regulated it in 118MGC and U373-MG cells. Mutation in five cAMP response elements (CREs) within the MIEP resulted in a loss of the ability to respond to MG132 in IMR-32 cells. Moreover, Western blotting analysis revealed that MG132 induced c-Jun phosphorylation in all three CNS-derived cell lines, whereas a high level of activating transcription factor-2 (ATF-2) phosphorylation was observed only in IMR-32 cells. Finally, MG132-induced MIE protein expression was suppressed by JNK inhibitor that reduced the phosphorylation levels of both c-Jun and ATF-2. Taken together, these results suggest that the proteasome inhibitors activate CRE binding proteins consisting of c-Jun and ATF-2 through activating the JNK-c-Jun pathway, thereby inducing MIE protein synthesis in IMR-32 cells under the condition where NF-kappaB activity is inhibited.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa, Ishikawa 920-1181, Japan. h-sadanari@hokuriku-u.ac.jp
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Sadanari
authors.forename: Junji
authors.initials: J
authors.lastname: Tanaka
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Li
authors.forename: Rie
authors.initials: R
authors.lastname: Yamada
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsubara
authors.forename: Tsugiya
authors.initials: T
authors.lastname: Murayama
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism / Q000821:virology*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D017874:Immediate-Early Proteins; D007783:Lactones; D007976:Leupeptins; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D016755:Proto-Oncogene Proteins c-jun; C098869:clasto-lactacystin beta-lactone; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C078846:epoxomicin