title: Clioquinol increases the expression of VGF, a neuropeptide precursor, through induction of c-Fos expression.
abstract: Clioquinol was used extensively in the mid-1900s as an amebicide to treat indigestion and diarrhea. It was eventually withdrawn from the market because it was linked to subacute myelo-optic neuropathy (SMON) in Japan. However, the pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of VGF (nonacronymic), the precursor of neuropeptides involved in pain reactions, was significantly increased when SH-SY5Y and IMR-32 neuroblastoma cells were treated with clioquinol. Promoter analyses in SH-SY5Y cells revealed that a region responsive to clioquinol exists between -1381 and -1349 of the human VGF gene, which contains an activator protein (AP)-1 site-like sequence. The introduction of mutations at this site significantly reduced clioquinol-induced transcriptional activation. Clioquinol induced the expression of the AP-1 family transcription factors, c-Jun and c-Fos. Electrophoresis mobility shift assays demonstrated that c-Jun and c-Fos could bind to the AP-1 site at -1374/-1368 in SH-SY5Y cells treated with clioquinol. RNA interference against c-Fos significantly suppressed clioquinol-induced VGF mRNA expression. These results suggest that the clioquinol-induced expression of c-Fos mediates the induction of VGF expression.
authors.affiliation: Radioisotope Center, Kyoto Prefectural University of Medicine, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Katsuyama
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ibi
authors.forename: Misaki
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ohshima
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
mesh_terms: D000563:Amebicides / Q000009:adverse effects / Q000494:pharmacology*; D007464:Clioquinol / Q000009:adverse effects / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D009187:Myelitis / Q000139:chemically induced; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009902:Optic Neuritis / Q000139:chemically induced; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000563:Amebicides; D009414:Nerve Growth Factors; D009479:Neuropeptides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C510637:VGF protein, human; D007464:Clioquinol