Unknown,Transcriptomics,Genomics,Proteomics

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Cyclin D1 Transgenic Mice with Bim-deficient B-cells

ABSTRACT: Expression analysis from a genetically engineered mouse model of mantle cell lymphoma (MCL) Gene expression was measured in fourteen mice that overexpress cyclin D1 and delete Bim in their B cells and that were stimulated with sheep red blood cells (SRBC) and irradiation (I), pristane (P) or only SRBC weekly (A). Mice that developed disease based on histopathologic criteria were compared to ones that did not. An additional seven stimulated mice that only overexpressed cyclin D1 were used to estimate the data set variance.

ORGANISM(S): Mus musculus

SUBMITTER: Hailong Meng

PROVIDER: E-GEOD-52214 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells.

Katz Samuel G SG Labelle James L JL Meng Hailong H Valeriano Regina P RP Fisher Jill K JK Sun Heather H Rodig Scott J SJ Kleinstein Steven H SH Walensky Loren D LD

Blood 20131218 6

Mantle cell lymphoma (MCL) is a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Indeed, several genetic aberrations have been identified in MCL that may contribute to its pathogenesis and chemoresistance. Of particular interest is the frequent biallelic deletion of the proapoptotic BCL-2 family protein BIM. BIM exert ...[more]

PMID: 24352880

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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 hypothesized that cyclin D1 may play role in transcription by interacting with transcriptional machinery at the promoters of target genes. To test this possibility, we employed chromatin immunoprecipitation coupled to DNA microarray analysis (genome-wide location analysis or ChIP-chip) to study association of cyclin D1 with genomic DNA sequences. In this procedure, a protein of interest is crosslinked to DNA, immunoprecipitated, and the bound DNA is hybridized to an array containing probes that span the genome. Since anti-FLAG antibodies have been successfully used for ChIP-chip in several different systems including murine cells, knock-in mice expressing tagged cyclin D1 provided us with a novel tool to query the association of cyclin D1 with the genome in vivo, in a living mouse.

Dataset Information

Cyclin D1 Transgenic Mice with Bim-deficient B-cells

Publications

Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells.

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