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Procaspase3-Cyclin D1 assembly rewires cancer cells from apoptosis to proliferation [in vitro]

ABSTRACT: Purpose: To gain insights into the activity of Cyclin D1 in tumor maintenance, we developed a specific RNAi strategy to knock down its expression and analyze the outcome on gene expression profile of RAS/DNP53-driven cancer cells (transformed MEFs). Cells were treated by RNAi or with Leptomycin B over night. Method: RAS/DNP53-transformed MEFs mRNA profiles were generated by RNA-Sequencing. Results: Cyclin D1 knock down in RAS-G12V-driven cancer cells leads to expression change of genes involved in developmental processes, but no change in FAS or FASL levels.

ORGANISM(S): Mus musculus

PROVIDER: GSE112105 | GEO | 2021/03/20

REPOSITORIES: GEO

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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.

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Procaspase3-Cyclin D1 assembly rewires cancer cells from apoptosis to proliferation [in vitro]

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