Abstract
1-Methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces cell death and inhibition of cell proliferation in various cells. However, the mechanism whereby MPP(+) inhibits cell proliferation is still unclear. In this study, we found that MPP(+) suppressed the proliferation with accumulation in G(1) phase without inducing cell death in p53-deficient MG63 osteosarcoma cells. MPP(+) induced hypophosphorylation of retinoblastoma protein and rapidly down-regulated the protein but not mRNA levels of cyclin D1 in MG63 cells. The down-regulation of cyclin D1 protein was suppressed by a proteasome inhibitor, MG132. The cyclin D1 down-regulation by MPP(+) was also observed in p53-positive PC12, HeLa S3, and HeLa rho(0) cells, which are a subclone of HeLa S3 lacking mitochondrial DNA. Moreover, MPP(+) dephosphorylated Akt in PC12 cells, which was rescued by the pretreatment with nerve growth factor. In addition, the pretreatment with nerve growth factor or lithium chloride, a glycogen synthase kinase-3beta inhibitor, suppressed the cyclin D1 down-regulation caused by MPP(+). Our results demonstrate that MPP(+) induces cell cycle arrest independently of its mitochondrial toxicity or the p53 status of the target cells, but rather through the proteasome- and phosphatidylinositol 3-Akt-glycogen synthase kinase-3beta-dependent cyclin D1 degradation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenylpyridinium / metabolism*
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Animals
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Blotting, Northern
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Blotting, Western
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Cell Cycle
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Cell Division
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Cell Line
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Cell Line, Tumor
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Cyclin D1 / metabolism*
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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DNA, Mitochondrial / metabolism
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Dose-Response Relationship, Drug
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Down-Regulation
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Flow Cytometry
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G1 Phase
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HeLa Cells
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Herbicides
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Humans
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Ions
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Leupeptins / pharmacology
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Mitochondria / metabolism
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Multienzyme Complexes / metabolism*
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PC12 Cells
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Phosphorylation
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Proteasome Endopeptidase Complex
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA Processing, Post-Transcriptional
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Rats
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Retinoblastoma Protein / metabolism
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Serine / chemistry
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Time Factors
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Tumor Suppressor Protein p53 / metabolism
Substances
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Cysteine Proteinase Inhibitors
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DNA, Mitochondrial
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Herbicides
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Ions
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Leupeptins
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Multienzyme Complexes
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Proto-Oncogene Proteins
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Retinoblastoma Protein
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Tumor Suppressor Protein p53
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Cyclin D1
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Serine
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AKT1 protein, human
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Akt1 protein, rat
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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1-Methyl-4-phenylpyridinium
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde