Regulation of S-phase transcription factors by Cdk1
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE55121 | GEO | 2014/04/10
SECONDARY ACCESSION(S): PRJNA238581
REPOSITORIES: GEO
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Project description:Analysis of gene expression across the cell cycle from wild type cells, and cells expressing alleles of Yox1, Yhp1, Hcm1, and Tos4 that cannot be phosphorylated by Cdk1. Expression of S-phase and M/G1 transcripts are downregulated when phosphorylation of these factors is blocked, demonstrating that Cdk1 promotes expression of late cell cycle genes. These experiments are two-color hybridizations of RNA isolated from synchronized wild type (WT) or phosphomutant (4P) cells, compared to RNA from asyncrhonous wild type cells in mid-log phase. Wild type and mutant cells were synchronized in G1 phase, released into the cell cycle and samples collected at 15 minute intervals. Each time course was carried out in duplicate, the replicate experiment was performed as a dye swap.
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Project description:We addressed the role of cell cycle regulator CDK1 during differentiation by either inhibiting its activity with the specific inhibitor RO3306 (10µM) or by knocking its expression down using specific shRNAs, during mesendoderm differentiation. Human pluripotent stem cells (H9 cells) were synchronized in their cell cycle and then induced to differentiate into mesendoderm for 24h. shRNAs against CDK1 were induced 4 days before starting the differentiation. The CDK1 inhibitor was added to the medium 8h after the induction of differentiation. At the end of the experiment, the cells were harvested and processed for total RNA extraction. RNA-IP was carried out using RiboCluster Profiler RIP-Assay Kit (MBL) following the manufacture’s recommendations.
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Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas that are sporadic or associated with NF1 gene mutations. Traditional therapies are `usually ineffective for treating MPNSTs, so new targets need to be identified for the treatment of MPNSTs. In the present study, the role of the mitochondrial translocator protein (TSPO) in the regulation of cell proliferation and the cell cycle in MPNSTs was investigated. TSPO expression was lower in MPNSTs than in NFs. Loss-of-function experiments revealed that TSPO deficiency promoted MPNST cell growth, migration, and invasion and influenced the cell cycle in vitro and in vivo. In addition, TSPO depletion suppressed cell apoptosis by downregulating the expression of caspase-3, caspase-8, HSP60, p27, p53, and BCL-2 and suppressed the cell cycle by upregulating CDK1, CDK2, CCNB1 and CCNA2. Furthermore, CDK1 was determined to be an upstream target of TSPO-mediated regulation via RNA-seq, qPCR, and Western blotting. Specifically, depletion of CDK1 weakened the effect of TSPO deficiency on cell proliferation and migration. More importantly, CDK1 knockdown induced significant cell cycle arrest in the G2/M phase. In summary, TSPO deficiency regulates the cell cycle in MPNSTs by targeting CDK1, which may be an effective molecular target for prognosis evaluation and treatment.
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Project description:We report gene expression data for yeast strains expressing mutated versions of the transcriptional repressors Yox1 and Yhp1 that can't be phosphorylated by Cdk1. For comparision, gene expression was also measured in cells with deletions in one or both repressors. Genes that are downregulatd in phosphomutant strains and upregulated in deletion strains are likely to be target genes of these transcriptional repressors.
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Project description:The retinoblastoma tumor suppressor protein (Rb) regulates early G1 phase checkpoints, including the DNA damage response, as well as cell cycle exit and differentiation. The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 partially inactivates the Rb tumor suppressor during early G1 phase by progressive multi-phosphorylation, termed hypo-phosphorylation, resulting in release of E2F transcription factors. However, this model remains largely unproven biochemically and the biologically active form(s) of Rb remains unknown. Here we find that Rb is un-phosphorylated in G0 cells and becomes exclusively mono-phosphorylated throughout all of early G1 phase by cyclin D:Cdk4/6. Early G1 phase mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but each shows a preferential binding pattern to specific E2F1-4 transcription factors. At the late G1 Restriction Point, cyclin E:Cdk2 inactivates Rb by a quantum hyper-phosphorylation (>12 phosphates/Rb). Cells undergoing a DNA damage response activate cyclin D:Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription. In contrast, a non-phosphorylatable ?Cdk-Rb allele was non-functional for regulating a DNA damage response, but functional for driving cell cycle exit and differentiation during myogenesis. These observations fundamentally change our understanding of G1 cell cycle progression and show that there is no progressive multi-phosphorylation or hypo-phosphorylation inactivation of Rb during early G1 phase by cyclin D:Cdk4/6. Instead, cyclin D:Cdk4/6 generates functionally active, mono-phosphorylated Rb that is the only Rb isoform present in cells during early G1 phase.
2014-04-03 | GSE56453 | GEO
Project description:The retinoblastoma tumor suppressor protein (Rb) regulates early G1 phase checkpoints, including the DNA damage response, as well as cell cycle exit and differentiation. The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 partially inactivates the Rb tumor suppressor during early G1 phase by progressive multi-phosphorylation, termed hypo-phosphorylation, resulting in release of E2F transcription factors. However, this model remains largely unproven biochemically and the biologically active form(s) of Rb remains unknown. Here we find that Rb is un-phosphorylated in G0 cells and becomes exclusively mono-phosphorylated throughout all of early G1 phase by cyclin D:Cdk4/6. Early G1 phase mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but each shows a preferential binding pattern to specific E2F1-4 transcription factors. At the late G1 Restriction Point, cyclin E:Cdk2 inactivates Rb by a quantum hyper-phosphorylation (>12 phosphates/Rb). Cells undergoing a DNA damage response activate cyclin D:Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription. In contrast, a non-phosphorylatable ?Cdk-Rb allele was non-functional for regulating a DNA damage response, but functional for driving cell cycle exit and differentiation during myogenesis. These observations fundamentally change our understanding of G1 cell cycle progression and show that there is no progressive multi-phosphorylation or hypo-phosphorylation inactivation of Rb during early G1 phase by cyclin D:Cdk4/6. Instead, cyclin D:Cdk4/6 generates functionally active, mono-phosphorylated Rb that is the only Rb isoform present in cells during early G1 phase. Global transcriptional analysis of murine embryonic fibroblasts (MEFs) with conditional deletion of the endogenous RB gene by treatment with cell permeable TAT-Cre. Comparison to unaltered MEFs and MEFs with physiological level of exogenous wildtype or phospho-mutant RB expressed at time of RB gene deletion.
2014-04-03 | E-GEOD-56453 | biostudies-arrayexpress
Project description:Two homeodomain proteins, Yox1 and Yhp1, act as repressors at early cell cycle boxes (ECBs) to restrict their activity to the M/G1 phase of the cell cycle in budding yeast. These proteins bind to Mcm1 and to a typical homeodomain binding site. The expression of Yox1 is periodic and directly correlated with its binding to, and repression of, ECB activity. The absence of Yox1 and Yhp1 or the constitutive expression of Yox1 leads to the loss of cell-cycle regulation of ECB activity. Therefore, the cell-cycle-regulated expression of these repressors defines the interval of ECB-dependent transcription. Twenty-eight genes, including MCM2-7, CDC6, SWI4, CLN3, and a number of genes required during late M phase have been identified that are coordinately regulated by this pathway. Keywords: cell cycle time course
2006-08-31 | GSE5283 | GEO
Project description:Biological Relevance and Intent of the Experiment: The objective of this study is to elucidate the role of Cdk1 in cardiac function, specifically its contribution to cardiomyocyte proliferation and response to injury. Using a heart-specific Cdk1 knockout mouse model, we investigate the molecular and cellular impact of Cdk1 deficiency in the context of myocardial infarction (MI). Cdk1 is known for its regulatory functions in cell cycle progression, and its absence may significantly affect cardiac repair mechanisms post-MI. This research aims to explore whether the lack of Cdk1 impairs cardiomyocyte regeneration or promotes maladaptive remodeling, leading to compromised cardiac function.
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Project description:Purpose: Determine whether Cdk1 only regulates a specific subset of tDNAs, or whether Cdk1 has a more global impact on tDNA expression; Method: We study the expression of tRNA genes in WT cells and cdk1-as1 mutants during S phase by small-RNAseq; Result: We found that expression of at least 77% of all tDNAs is significantly downregulated in S-phase in the cdk1-as1 mutant compared with the WT strain; Conclussions: Cdk1 promotes transcription of the majority of tRNA genes during the cell cycle.
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