Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Loss-of-parkin function enhances cyclin D1 expression and AKT signalling and promotes glioblastoma cell proliferation

ABSTRACT: Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major cause of autosomal recessive parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor. Consistent with this, the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we show that parkin expression is dramatically reduced in glioma cells, which correlates with increased cancer mortality. We further show that restoration of parkin expression in these cells promotes their arrest at G1 phase and significantly mitigates their proliferation rate both in vitro and in vivo. Notably, the level of cyclin D1, but not cyclin E, is reduced in parkin-expressing glioma cells. Moreover, parkin expression also leads to a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. Supporting this, cells derived from parkin null mouse exhibit increased levels of cyclin D1, VEGF receptor and Akt phosphorylation and divide significantly faster compared to their wild type counterparts. Importantly, analysis of parkin pathway activation revealed its predictive power for survival outcome of glioma patients. Taken together, our study provides a mechanism by which parkin exerts its tumor suppressor function and a signature pathway of parkin that is of potential prognostic value. Total RNA obtained from U-87MG cells stably expressing parkin or vector alone. Replicate arrays were performed for each of the 3 vector and parkin-expressing U-87MG clones.

ORGANISM(S): Homo sapiens

SUBMITTER: Felicia Ng

PROVIDER: E-GEOD-29494 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival.

Yeo Calvin W S CW Ng Felicia S L FS Chai Chou C Tan Jeanne M M JM Koh Geraldene R H GR Chong Yuk Kien YK Koh Lynnette W H LW Foong Charlene S F CS Sandanaraj Edwin E Holbrook Joanna D JD Ang Beng-Ti BT Takahashi Ryosuke R Tang Carol C Lim Kah-Leong KL

Cancer research 20120319 10

Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major genetic cause of parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor, and the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we investigated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells. Restoration of parkin expression promoted G(1) phase cell-cycle ar ...[more]

PMID: 22431710

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Project description:Cyclin D1 belongs to the core cell cycle machinery1, and it is frequently overexpressed in human cancers2. The full repertoire of cyclin D1 functions in normal development and in cancer cells is currently unknown. To address this question, here we introduce a novel approach that allows one to determine the set of cyclin D1-interacting proteins (D1 âinteractomeâ) and cyclin D1-bound genomic fragments (D1 âcistromeâ) in essentially any mouse organ, at any point of development or at any stage of cancer progression. Using this approach, we detected several novel tissue-specific interactors of cyclin D1. A significant number of these partners represent proteins involved in transcription. We show, using genome-wide location analysis3, that cyclin D1 occupies promoters of a very large number of genes in the developing mouse, where it binds in close proximity to transcription start sites. Bioinformatics analyses of cyclin D1-bound genomic segments in the developing embryo revealed DNA recognition sequences for several transcription factors. By querying SAGE libraries4, promoter CpG content5 and gene expression profiles of cyclin D1-null organs, we demonstrate that cyclin D1 binds promoters of highly expressed genes, and that it functions to activate or to repress gene expression in vivo. Analyses of cyclin D1 transcriptional targets reveal that cyclin D1 contributes to cell proliferation by upregulating genes required for S-phase entry and progression. Hence, cyclin D1 plays a broad transcriptional regulatory function in vivo during normal mouse development. We wished to determine whether cyclin D1 functioned to positively or negatively regulate transcription of the target genes (identified by chip-on-chip) in vivo. To address this question, we asked how expression of cyclin D1-bound genes changes when cyclin D1 has been knocked-out. We dissected retinas from eyes of cyclin D1-/- or wild-type neonates, isolated RNA and hybridized it onto Affymetrix expression arrays.

Dataset Information

Loss-of-parkin function enhances cyclin D1 expression and AKT signalling and promotes glioblastoma cell proliferation

Publications

Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival.

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