Proteasome inhibitor differentially regulates expression of the major immediate early genes of human cytomegalovirus in human central nervous system-derived cell lines

Virus Res. 2009 Jun;142(1-2):68-77. doi: 10.1016/j.virusres.2009.01.010. Epub 2009 Feb 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2 / genetics
  • Activating Transcription Factor 2 / metabolism
  • Cell Line
  • Central Nervous System / metabolism
  • Central Nervous System / virology*
  • Cytomegalovirus / drug effects*
  • Cytomegalovirus / genetics
  • Cytomegalovirus / metabolism
  • Cytomegalovirus Infections / genetics
  • Cytomegalovirus Infections / metabolism
  • Cytomegalovirus Infections / virology*
  • Gene Expression Regulation, Viral / drug effects*
  • Humans
  • Immediate-Early Proteins / genetics*
  • Immediate-Early Proteins / metabolism
  • Lactones / pharmacology
  • Leupeptins / pharmacology
  • Oligopeptides / pharmacology
  • Protease Inhibitors / pharmacology*
  • Proteasome Inhibitors*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism


  • Activating Transcription Factor 2
  • Immediate-Early Proteins
  • Lactones
  • Leupeptins
  • Oligopeptides
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-jun
  • clasto-lactacystin beta-lactone
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • epoxomicin