Viral persistent infection affects both transcriptional and posttranscriptional regulation of neuron-specific molecule GAP43.
Recently, we reported that in vitro and in vivo persistent infection of neurons by lymphocytic choriomeningitis virus (LCMV) downregulated GAP43 expression, a protein involved in neuronal plasticity associated with learning and memory. Here, we investigated the transcriptional and posttranscriptional events involved. Persistent LCMV infection of PC12 cells (PC12Pi) caused reduced levels of GAP43 steady-state mRNA when compared to uninfected PC12 cells. In addition, an increase in the steady-state levels of GAP43 mRNA observed in PC12 cells in response to nerve growth factor (NGF) was abrogated in PC12Pi cells. Nuclear run-on analysis revealed that the rate of GAP43 transcription was reduced threefold in PC12Pi cells compared to uninfected PC12 cells. Moreover, analysis of the half-life of GAP43 mRNA indicated that NGF-mediated stabilization of GAP43 transcripts was significantly diminished in PC12Pi cells. Treatment of PC12Pi cells with basic fibroblast growth factor, dibutyryl cyclic AMP, and 12-o-tetradecanoyl-phorbol-13-acetate, a potent activator of protein kinase C, did not increase the GAP43 mRNA steady-state level, suggesting that LCMV infection interferes with a step downstream from protein kinases A and C in the NGF signal transduction pathway.
Cao
W
W
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037, USA.
Oldstone
M B
MB
De La Torre
J C
JC
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D019922:GAP-43 Protein; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons; D016716:PC12 Cells; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D017735:Virus Latency
D019922:GAP-43 Protein; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger