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Procaspase 3-Cyclin D1 assembly rewires cancer cells from apoptosis to proliferation

ABSTRACT: Purpose: To gain insights into the activity of Cyclin D1 in tumor maintenance, we developed a cancer cell-specific RNAi strategy to knock down its expression and analyze the outcome on gene expression profile of the entire tumor. Method: RAS/DNP53-driven tumor mRNA profiles were generated by RNA-Sequencing. Reads from RNA-Seq samples were mapped to the Mus musculus reference genome (MGSCv37) using Bowtie and TopHat. Transcript abundance and differential expression were called by Cufflinks. Results: Cyclin D1 knock down in RAS-G12V or MMTV-ErbB2-driven tumors leads to expression change of genes involved in developmental processes, but no significant change in apoptotic genes was recorded among the samples.

ORGANISM(S): Mus musculus

PROVIDER: GSE63578 | GEO | 2020/04/11

REPOSITORIES: GEO

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

Project description: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.

2021-03-20 | GSE112105 | GEO

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

Project description: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 the entire tumor. Method: MMTV-ErbB2 or RAS/DNP53-driven tumor mRNA profiles were generated by RNA-Sequencing. Results: Cyclin D1 knock down in RAS-G12V or MMTV-ErbB2-driven tumors leads to expression change of genes involved in developmental processes, but no change in FAS or FASL levels.

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Transcription profiling of mouse NIH3T3 cells were compared with myc/ras transformed NIH3T3 cells and with IRF1 expressing myc/ras transformed cells

Project description:Interferons have been ascribed to mediate antitumor effects. IRF-1 is a major target gene of interferons. It inhibits cell proliferation and oncogenic transformation. Here we show that 60% of all mRNAs deregulated by oncogenic transformation mediated by c-myc and H-ras are reverted to the expression levels of non-transformed cells by IRF-1. These include cell cycle regulating genes. Activation of IRF-1 decreases cyclin D1 expression and CDK4 kinase activity concomitant with dephosphorylation of pRb. These effects of IRF-1 are mediated by inhibition of the MEK-ERK pathway and a transcriptional repression of cyclin D1. IRF-1 mediated effects on cell cycle progression were found to be overridden by ectopic expression of cyclin D1. Ablation of cyclin D1 by RNA interference experiments prevents transformation and tumor growth in nude mice. The data demonstrate that cyclin D1 is a key target for IRF-1 mediated tumor suppressive effects. Experiment Overall Design: 3 samples were analysed, two replicates per sample. NIH3T3 cells were compared with myc/ras transformed NIH3T3 cells and with IRF1 expressing myc/ras transformed cells.

2008-06-14 | E-GEOD-6505 | biostudies-arrayexpress

Non-phosphorylatable cyclin D1 mutant potentiates endometrial hyperplasia and drives carcinoma with Pten loss

Project description:Cyclin D1 is a regulatory subunit of cyclin-Dependent Kinases 4 and 6 (CDK4/6) and regulates progression from G1 to S phase of the cell cycle. Dysregulated cyclin D1-CDK4/6 contributes to tumor development. Enforced expression of non-phosphorylatable cyclin D1T286A mutant, frequently observed in human cancers, drives tumorigenesis. However, physiological functions of cyclin D1T286A is unclear. We have generated a conditional knock-in mouse model where cyclin D1T286A is expressed under the control of its endogenous promoter, permitting us to study the precise functions of cyclin D1T286A in tumorigenesis. The expression of cyclin D1T286A from its endogenous promoter induces inflammation-mediated lymphocyte disorder and mesenteric tumor formation. Uterine-specific expression of cyclin D1T286A accelerates Pten loss driven endometrial hyperplasia to promote uterine cancer.

2023-04-04 | GSE188299 | GEO

Tumor suppression by Interferon regulatory factor-1 relies on down-regulation of cyclin D1

Project description:Interferons have been ascribed to mediate antitumor effects. IRF-1 is a major target gene of interferons. It inhibits cell proliferation and oncogenic transformation. Here we show that 60% of all mRNAs deregulated by oncogenic transformation mediated by c-myc and H-ras are reverted to the expression levels of non-transformed cells by IRF-1. These include cell cycle regulating genes. Activation of IRF-1 decreases cyclin D1 expression and CDK4 kinase activity concomitant with dephosphorylation of pRb. These effects of IRF-1 are mediated by inhibition of the MEK-ERK pathway and a transcriptional repression of cyclin D1. IRF-1 mediated effects on cell cycle progression were found to be overridden by ectopic expression of cyclin D1. Ablation of cyclin D1 by RNA interference experiments prevents transformation and tumor growth in nude mice. The data demonstrate that cyclin D1 is a key target for IRF-1 mediated tumor suppressive effects. Keywords: NIH3T3 cells, myc, ras, IRF-1, proliferation, transformation, G1/S cell cycle ceckpoint

2006-12-16 | GSE6505 | GEO

A Novel Pro-Survival Function of Cyclin-D1 Underlies Its Oncogenic Role and Potential as a Therapeutic Target in Human and Murine Mantle Cell Lymphoma

Project description:The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 over-expression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current therapies. Cyclin-D1 has been postulated as an effective therapeutic target, but its evaluation has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1-driven mouse model whereby cyclin-D1 expression can be externally regulated. These mice developed lymphomas capable of recapitulating most features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo. However, using a combination of in vitro and in vivo assays, we identified a novel pro-survival cyclin-D1 function in MCL cells. Specifically, we demonstrate that cyclin-D1 sequestrates the pro-apoptotic protein BAX, thereby favoring BCL2 anti-apoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a pro-apoptotic BH3 mimetic synergistically killed murine lymphomas and human MCL cells. Our study identifies a novel role of cyclin-D1 in deregulating apoptosis and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL.

2011-07-01 | GSE25613 | GEO

Gene expression profiles of Ras mutants.

2009-02-21 | GSE14934 | GEO

Gene expression profiles of Ras mutants.

Project description:Gene expression profiles were collected from HEK-HT cells expressing H-Ras with Ras-activating (G12V), Raf-activating (G12V,T35S), RalGEF-activating (G12V,E37G), or PI3K-activating (G12V,Y40C) mutations. Keywords: Comparison of Ras pathway components. THX=control; 12V=G12V mutation; 35S=G12V,T35S mutation; 37G=G12V,E37G mutation; 40C=G12V,Y40C mutation. 5 replicates of each. Total of 25 samples.

2009-02-21 | E-GEOD-14934 | biostudies-arrayexpress

A Novel Pro-Survival Function of Cyclin-D1 Underlies Its Oncogenic Role and Potential as a Therapeutic Target in Human and Murine Mantle Cell Lymphoma

2011-07-01 | E-GEOD-25613 | biostudies-arrayexpress

The undifferentiated phenotype in neuroblastoma depends on Cyclin D1 and CDK4 activity

Project description:Genomic aberrations of Cyclin D1 (CCND1) and CDK4 in neuroblastoma indicate that dysregulation of the G1 entry checkpoint is an important cell cycle aberration in this pediatric tumor. Here we report that analysis of Affymetrix expression data of primary neuroblastic tumors shows an extensive over-expression of Cyclin D1 and CDK4 which correlates with histological subgroups and prognosis respectively. Immunohistochemical analysis demonstrated an over-expression of Cyclin D1 in neuroblasts and a low Cyclin D1 expression in all cell types in ganglioneuroma. This suggests an involvement of G1 regulating genes in neuronal differentiation processes which we further evaluated using RNA interference against Cyclin D1 and its kinase partner CDK4 in several neuroblastoma cell lines. This resulted in pRb pathway inhibition as shown by an almost complete disappearance of CDK4 specific pRb phosphorylation; reduction of E2F transcriptional activity and a decrease of Cyclin A protein levels. The Cyclin D1 and CDK4 knock-down resulted in a significant reduction in cell proliferation, a G1 specific cell cycle arrest and moreover an extensive neuronal differentiation. Affymetrix microarray profiling of siRNA treated cells revealed a shift in expression profile towards a neuronal phenotype. Several new potential downstream players are identified. We conclude that neuroblastoma functionally depend on over-expression of G1 regulating genes to maintain their undifferentiated phenotype. Keywords: Neuroblastoma, CCND1, Cyclin D1, CDK4

2008-08-20 | GSE8866 | GEO

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