Cell cycle aberrations by α-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies

Lee, S S; Kim, Y M; Junn, Eunsung; Lee, G; Kh, Park; Tanaka, Mikiei; Ronchetti, Ruben; Quezado, Martha; Mouradian, M. Maral

doi:10.1016/s0197-4580(02)00196-3

Cited by 73 publications

(53 citation statements)

References 75 publications

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“…Our results are in line with the former reports and further suggest that down-regulation of UPS by ␣-syn may play an important role for cells to escape from cell cycle and commit to cellular differentiation. Although little has been documented regarding the role of ␣-syn for cell cycle, Lee et al (57) previously showed that inducible expression of ␣-syn in PC12 cells resulted in enhanced proliferation rates through stimulation of ERK pathway whereby cells were enriched in the S phase associated with increased accumulation of cyclin B and down-regulation of Rb (57). The reason for the apparent discrepancy between the report by Lee et al (57) and our present study is obscure.…”

Section: Discussioncontrasting

confidence: 83%

“…Although little has been documented regarding the role of ␣-syn for cell cycle, Lee et al (57) previously showed that inducible expression of ␣-syn in PC12 cells resulted in enhanced proliferation rates through stimulation of ERK pathway whereby cells were enriched in the S phase associated with increased accumulation of cyclin B and down-regulation of Rb (57). The reason for the apparent discrepancy between the report by Lee et al (57) and our present study is obscure. However, one possible explanation is that effects of ␣-syn on growth and differentiation might be cell type-specific.…”

Section: Discussioncontrasting

confidence: 83%

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α-Synuclein Stimulates Differentiation of Osteosarcoma Cells

Fujita

Sugama

Nakai

et al. 2007

Journal of Biological Chemistry

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Because a limited study previously showed that ␣-synuclein (␣-syn), the major pathogenic protein for Parkinson disease, was expressed in differentiating brain tumors as well as various peripheral cancers, the main objective of the present study was to determine whether ␣-syn might be involved in the regulation of tumor differentiation. For this purpose, ␣-syn and its non-amyloidogenic homologue ␤-syn were stably transfected to human osteosarcoma MG63 cell line. Compared with ␤-syn-overexpressing and vector-transfected cells, ␣-syn-overexpressing cells exhibited distinct features of differentiated osteoblastic phenotype, as shown by up-regulation of alkaline phosphatase and osteocalcin as well as inductive matrix mineralization. Further studies revealed that proteasome activity was significantly decreased in ␣-syn-overexpressing cells compared with other cell types, consistent with the fact that proteasome inhibitors stimulate differentiation of various osteoblastic cells. In ␣-syn-overexpressing cells, protein kinase C (PKC) activity was significantly decreased, and reactivation of PKC by phorbol ester significantly restored the proteasome activity and abrogated cellular differentiation. Moreover, activity of lysosome was up-regulated in ␣-syn-overexpressing cells, and treatment of these cells with autophagy-lysosomal inhibitors resulted in a decrease of proteasome activity associated with up-regulation of ␣-syn expression, leading to enhance cellular differentiation. Taken together, these results suggest that the stimulatory effect of ␣-syn on tumor differentiation may be attributed to down-regulation of proteasome, which is further modulated by alterations of various factors, such as protein kinase C signaling pathway and a autophagy-lysosomal degradation system. Thus, the mechanism of ␣-syn regulation of tumor differentiation and neuropathological effects of ␣-syn may considerably overlap with each other.

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Section: Discussioncontrasting

confidence: 83%

Section: Discussioncontrasting

confidence: 83%

α-Synuclein Stimulates Differentiation of Osteosarcoma Cells

Fujita

Sugama

Nakai

et al. 2007

Journal of Biological Chemistry

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“…Amplifications of 4q are frequent in CTCL (40), and in our integrated analysis, 4q turned out to be one of the areas with overexpressed genes and DNA copy number amplifications. Overexpression of SNCA has been shown to increase cell proliferation (41). The MMP-9 was overexpressed in Sezary syndrome and mycosis fungoides PBMC samples.…”

Section: Discussionmentioning

confidence: 98%

Th1 Response and Cytotoxicity Genes Are Down-Regulated in Cutaneous T-Cell Lymphoma

Hahtola

Tuomela

Elo

et al. 2006

Clinical Cancer Research

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Purpose: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes. Experimental Design: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4+ cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression. Results: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations. Conclusions: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.

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“…Likewise, UCH-L1 (Park5) demonstrates abnormal expression in cancer that correlates with tumor severity (34) and may contribute to the degradation of tumor suppressor Kip1 (35). Last of all, overexpression of ␣-synuclein (Park1) results in increased cellular proliferation rates and an increase in the number of cells in the S phase (36). Thus, a provocative link between PD, the UPS, and cell cycle control is demonstrated on both a genetic and functional level.…”

Section: Discussionmentioning

confidence: 99%

N-myc Regulates Parkin Expression

West¹,

Kapatos

O’Farrell

et al. 2004

Journal of Biological Chemistry

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Mutations in the parkin gene are common in earlyonset and familial Parkinson's disease (PD), and the parkin protein interacts in the ubiquitin-proteasome system as an E3 ligase. However, the regulatory pathways that govern parkin expression are unknown. In this study, we showed that a phylogenetically conserved N-myc binding site in the bi-directional parkin promoter interacted with myc-family transcription factors in reporter assays, and N-myc bound to the parkin promoter in chromatin immunoprecipitation assays and repressed transcription activity. Parkin expression was inversely correlated with N-myc levels in the developing mouse and human brain, in human neuroblastoma cell lines with various levels of n-myc amplification, and in an inducible N-myc cell line. Although parkin and N-myc expression were dramatically altered upon retinoic acid-induced differentiation of a human neuroblastoma cell line, modulation of parkin expression did not significantly affect either rates of cellular proliferation or levels of cyclin E. Analysis of additional genes associated with familial PD revealed a shared basis of transcription regulation mediated by N-myc and the cell cycle. Our results, in combination with functional knowledge of the proteins encoded by these genes, suggest a common pathway linking together PD, the ubiquitin-proteasome system, and cell cycle control.

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Cell cycle aberrations by α-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies

Cited by 73 publications

References 75 publications

α-Synuclein Stimulates Differentiation of Osteosarcoma Cells

α-Synuclein Stimulates Differentiation of Osteosarcoma Cells

Th1 Response and Cytotoxicity Genes Are Down-Regulated in Cutaneous T-Cell Lymphoma

N-myc Regulates Parkin Expression

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