Proteasome-dependent degradation of cyclin D1 in 1-methyl-4- phenylpyridinium ion (MPP+)-induced cell cycle arrest

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 G1 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 ρ° 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-3β 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-3β-dependent cyclin D1 degradation.