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Gene expression profile of mouse breast cancer V720 cells treated with vehicle or PD 0332991

ABSTRACT: D-cyclins represent components of cell cycle machinery. To test the efficacy of targeting D-cyclins in cancer treatment, we engineered mouse strains which allow acute and global ablation of individual D-cyclins in a living animal. Ubiquitous shutdown of cyclin D1 or inhibition of cyclin D associated kinase activity in mice bearing ErbB2-driven mammary carcinomas halted cancer progression and triggered tumor-specific senescence, without compromising the animals' health. Ablation of cyclin D3 in mice bearing T-cell acute lymphoblastic leukemias (T-ALL) triggered tumorspecific apoptosis. Such selective killing of leukemic cells can be also achieved by inhibiting cyclin D associated kinase activity in mouse and human T-ALL models. Hence, contrary to what one might expect from ablation of a cell cycle protein, acute shutdown of a D-cyclin leads not only to cell cycle arrest, but it also triggers tumor cell senescence or apoptosis, and it affects different tumor types through distinct cellular mechanisms. Inhibiting cyclin D-activity represents a highly-selective anticancer strategy which specifically targets cancer cells without significantly affecting normal tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE40513 | GEO | 2012/10/16

SECONDARY ACCESSION(S): PRJNA174205

REPOSITORIES: GEO

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Gene expression profile of mouse breast cancer V720 cells treated with vehicle or PD 0332991

Project description:D-cyclins represent components of cell cycle machinery. To test the efficacy of targeting D-cyclins in cancer treatment, we engineered mouse strains which allow acute and global ablation of individual D-cyclins in a living animal. Ubiquitous shutdown of cyclin D1 or inhibition of cyclin D associated kinase activity in mice bearing ErbB2-driven mammary carcinomas halted cancer progression and triggered tumor-specific senescence, without compromising the animals' health. Ablation of cyclin D3 in mice bearing T-cell acute lymphoblastic leukemias (T-ALL) triggered tumorspecific apoptosis. Such selective killing of leukemic cells can be also achieved by inhibiting cyclin D associated kinase activity in mouse and human T-ALL models. Hence, contrary to what one might expect from ablation of a cell cycle protein, acute shutdown of a D-cyclin leads not only to cell cycle arrest, but it also triggers tumor cell senescence or apoptosis, and it affects different tumor types through distinct cellular mechanisms. Inhibiting cyclin D-activity represents a highly-selective anticancer strategy which specifically targets cancer cells without significantly affecting normal tissues. Mouse breast cancer V720 cells were cultured in the presence of the CDK4/6 inhibitor PD 0332991 (PD; 1 microM) or vehicle (VO) for 24 hrs. Experiment was done in biological triplicate. A total of 6 RNA samples (3 vehicle treated and 3 PD 0332991 treated samples) were used for microarray expression analysis.

2012-10-16 | E-GEOD-40513 | biostudies-arrayexpress

Gene expression profile of human T-ALL cell line KOPTK1 treated with vehicle or PD 0332991

Project description:D-cyclins represent components of cell cycle machinery. To test the efficacy of targeting D-cyclins in cancer treatment, we engineered mouse strains which allow acute and global ablation of individual D-cyclins in a living animal. Ubiquitous shutdown of cyclin D1 or inhibition of cyclin D associated kinase activity in mice bearing ErbB2-driven mammary carcinomas halted cancer progression and triggered tumor-specific senescence, without compromising the animals' health. Ablation of cyclin D3 in mice bearing T-cell acute lymphoblastic leukemias (T-ALL) triggered tumorspecific apoptosis. Such selective killing of leukemic cells can be also achieved by inhibiting cyclin D associated kinase activity in mouse and human T-ALL models. Hence, contrary to what one might expect from ablation of a cell cycle protein, acute shutdown of a D-cyclin leads not only to cell cycle arrest, but it also triggers tumor cell senescence or apoptosis, and it affects different tumor types through distinct cellular mechanisms. Inhibiting cyclin D-activity represents a highly-selective anticancer strategy which specifically targets cancer cells without significantly affecting normal tissues. A human T-ALL cell line KOPTK1 cells were cultured in the presence of the CDK4/6 inhibitor PD 0332991 (PD; 1 microM) or vehicle (VO) for 48 hrs. Experiment was done in biological triplicate. A total of 6 RNA samples (3 vehicle treated and 3 PD 0332991 treated samples) were used for microarray expression analysis.

2012-10-16 | E-GEOD-40512 | biostudies-arrayexpress

Gene expression profile of human T-ALL cell line KOPTK1 treated with vehicle or PD 0332991

2012-10-16 | GSE40512 | GEO

A divergent cyclin/cyclin-dependent kinase complex controls the atypical replication of Plasmodium berghei during gametogony and parasite transmission.

Project description:Cell cycle transitions are generally triggered by variation in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria-causing parasites have a life cycle with unique cell-division cycles, and a repertoire of divergent CDKs and cyclins of poorly understood function and interdependency. We show that Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical regulator of atypical mitosis in the gametogony and is required for mosquito transmission. It phosphorylates canonical CDK motifs of components in the pre-replicative complex and is essential for DNA replication. We also provide evidence for indirect regulation of the concomitant M-phase progression. During a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2), although we obtained no evidence of SOC2 cycling by transcription, translation or degradation. Our results provide evidence that during Plasmodium male gametogony, this unique cyclin/CDK pair fills the functional space of multiple eukaryotic cell-cycle kinases controlling DNA replication and M-phase progression.

2020-06-17 | PXD017622 | Pride

A unique and divergent cyclin/cyclin-dependent kinase complex controls DNA replication during atypical cell-cycles of Plasmodium berghei gametogonyA unique and divergent cyclin/cyclin-dependent kinase complex controls DNA replication during atypical cell-cycles of Plasmodium berghei gametogony

Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria parasites express ancestral CDKs and cyclins, whose functions and interdependency remain elusive. Here, we show that the unique Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It is essential for DNA replication and phosphorylates canonical S/TPxK CDK motifs on components of the pre-replicative complex otherwise regulated by distinct kinases in other eukaryotes. Over a replicative cycle, CRK5 stably interacts with a single Haemosporidia-specific cyclin (SOC2) with no evidence of SOC2 degradation. Regulation of CRK5 activity relies instead on dynamic phosphorylation of a C-terminus extension that mediates its interaction with SOC2. Our results present evidence that during the atypical cell cycles of Plasmodium gametogony, a unique and divergent cyclin/CDK pair fulfils the functional space of multiple eukaryotic cell-cycle kinases to initiate DNA replication.

2020-02-18 | PXD017283 | Pride

A divergent cyclin/cyclin-dependent kinase complex controls progression through the atypical replicative cycles during Plasmodium berghei gametogony

Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria-causing parasites have evolved unique cell-cycles with a repertoire of ancestral CDKs and cyclins whose functions and interdependency remain elusive. Here, we show that the divergent Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It phosphorylates canonical CDK motifs on components of the pre-replicative complex and is essential for DNA replication. We also provide evidence for indirect regulation of the concomitant progression through M-phase. Over a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2) with no evidence of SOC2 cycling through transcription, translation nor degradation. Our results present evidence that during Plasmodium gametogony, a unique and divergent cyclin/CDK pair evolved to fulfil the functional space of multiple eukaryotic cell-cycle kinases controlling S-phase entry and progression through M-phase.

2020-02-25 | PXD017308 | Pride

A divergent cyclin/cyclin-dependent kinase complex controls progression through the atypical replicative cycles during Plasmodium berghei gametogony

2020-06-17 | GSE144743 | GEO

Budding yeast relies on qualitative G1 cyclin specificity to couple cell cycle progression with morphogenetic development

Project description:Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities associated with successive waves of G1, S and mitotic cyclins. Alternatively, the gradual quantitative rise of Cdk activity from G1 phase to mitosis could lead to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in the budding yeast S. cerevisiae. S-phase cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. The single cyclin can in addition replace G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot sustain proliferation. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.

2021-08-23 | PXD022757 | Pride

CDK11 requires a critical activator SAP30BP to regulate pre-mRNA splicing

Project description:CDK11 is an emerging druggable target for cancer therapy due to its prevalent roles in phosphorylating critical transcription and splicing factors and in facilitating cell cycle progression in cancer cells. Like other cyclin-dependent kinases, CDK11 requires its cognate cyclin, cyclin L1 or cyclin L2, for activation. However, little is known about how CDK11 activities might be modulated by other regulators. In this study, we show that CDK11 forms a tight complex with cyclins L1/L2 and SAP30BP, the latter of which is a poorly characterized factor. Acute degradation of SAP30BP mirrors that of CDK11 in causing widespread and strong defects in pre-mRNA splicing. Furthermore, we demonstrate that SAP30BP facilitates CDK11 kinase activities in vitro and in vivo, through ensuring the stabilities and the assembly of cyclins L1/L2 with CDK11. Together, these findings uncover SAP30BP as a critical CDK11 activator that regulates global pre-mRNA splicing.

2023-10-05 | GSE226804 | GEO

Transcription profiling of mouse embryonic fibroblasts from FHL2-/- and wild type animals

Project description:The LIM-only protein FHL2 acts as a transcriptional modulator that positively or negatively regulates multiple signaling pathways. We recently reported that FHL2 cooperates with CBP/p300 in the activation of Ã-catenin/TCF target gene cyclin D1. In this paper, we demonstrate that FHL2 is associated with the cyclin D1 promoter at the TCF/CRE site, providing evidence that cyclin D1 is a direct target of FHL2. We show that deficiency of FHL2 greatly reduces the proliferative capacity of spontaneously immortalized mouse fibroblasts which is associated with decreased expression of cyclin D1 and p16INK4a, and hypophosphorylation of Rb. Reexpression of FHL2 in FHL2-null fibroblasts efficiently restores cyclin D1 levels and cell proliferative capacity, indicating that FHL2 is critical for cyclin D1 activation and cell growth. Moreover, ectopic cyclin D1 expression is sufficient to override growth inhibition of immortalized FHL2-null fibroblasts. Gene expression profiling revealed that FHL2 deficiency triggers a broad change of the cell cycle program that is associated with downregulation of several G1/S and G2/M cyclins, E2F transcription factors and DNA replication machinery, thus correlating with reduced cell proliferation. This change also involves downregulation of the negative cell cycle regulators, particularly INK4 inhibitors, which could counteract the decreased expression of cyclins, allowing cells to grow. Our study illustrates that FHL2 can act on different aspects of the cell cycle program to finely regulate cell proliferation. Experiment Overall Design: Two biological genotypes, FHL2-/- and WT MEF cells. Three spontaneously immortalized clones of each genotype were analyzed using Affymetrix arrays.

2008-06-18 | E-GEOD-10902 | biostudies-arrayexpress

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