Analysis of the effect of clofarabine treatment on gene expression in K562 cells using mRNA sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE81455 | GEO | 2021/05/02
REPOSITORIES: GEO
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Project description:This 133-node Boolean regulatory network model reproduces mitochondrial dynamics during cell cycle progression (hyper-fusion at the G1/S boundary, fission in mitosis), apoptosis (fission and dysfunction) and glucose starvation (reversible hyper-fusion), as well as MiDAS in response to SIRT3 knockdown or oxidative stress and the protective role of NAD+ or external pyruvate. These features are in addition to the cell cycle-related phenotypes reproduced by the Sizek et al model that served as our starting point. Testable predictions (new): a) In cell lines with low basal p21 expression known to pre-commit to the next division in early mitosis of their current cycle, a subset of cells respond to glucose withdrawal by arresting with 4N DNA content but losing their internal G2 state (i.e. Cyclin A/B expression), and undergo endo-reduplication upon glucose re-exposure. b) In a subset of glucose-starved cells that pass the G2/M checkpoint with hyperfused mitochondria, mitotic fragmentation can be sufficiently delayed to cause spindle assembly defects and mitotic catastrophe. c) Quiescent cells are less susceptible to ROS-induced MiDAS due to FoxO-mediated PINK1 expression, which blocks MFN1/2 from inducing hyperfusion. d) Boosting NAD+ levels in MiDAS cells that have not yet established deep senescence (2-3 days post induction) can reverse their fate.
2024-08-26 | MODEL2312140001 | BioModels
Project description:Pluripotent embryonic stem cells have a unique cell cycle structure with a suppressed G1/S restriction point and little differential expression across the cell cycle phases. Here, we evaluate the link between G1/S restriction point activation, phasic gene expression, and cellular differentiation. Expression analysis reveals a gain in phasic gene expression across lineages between embryonic days E7.5 and E9.5. Genetic manipulation of the G1/S restriction point regulators miR-302 and P27 respectively accelerates or delays the onset of phasic gene expression in mouse embryos. Relief of miR-302-mediated p21 or p27 suppression expedites embryonic stem cell differentiation, while a constitutive Cyclin E mutant blocks it. Together, these findings uncover a causal relationship between emergence of the G1/S restriction point with a gain in phasic gene expression and cellular differentiation.
2022-05-02 | GSE142215 | GEO
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
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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2020-03-23 | GSE133857 | GEO
Project description:Lipid synthesis must increase during the cell cycle to double membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis in non-transformed cells. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic failure and cell death, which are triggered by low lipid synthesis much later in mitosis.
2024-02-22 | GSE254479 | 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.
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:We previously identified SMIP004 (N-(4-butyl-2-methyl-phenyl) acetamide), as a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, such as cyclin A, CDK4 and SKP2 while upregulating cyclin-dependent kinase inhibitors p27 and p21, resulting in G1 arrest and inhibition of colony formation in soft agar. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. We used profiling to unravel a SMIP004-induced pro-apoptotic pathway, which initiates with bioenergetic reprogramming at the level of mitochondria. SMIP004 causes downregulation of aerobic glycolysis, rapid upregulation of components of the mitochondrial electron transport chain, and oxidative stress. The latter, in turn, elicits cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation, drives transcriptional downregulation of the androgen receptor, and activates pro-apoptotic signaling through the unfolded protein response and MAPK activation. Finally SMIP004 was found to potently inhibit the growth of prostate and breast cancer xenografts in mice.
2015-12-16 | GSE48056 | GEO
Project description:Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Cyclin C was cloned as a growth-promoting G1 cyclin1,2, and several studies postulated a role for cyclin C in driving cell proliferation3-8 . Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression9-13. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase14, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice.
2017-03-29 | MSV000080728 | MassIVE