Mus musculus
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ABSTRACT:
PROVIDER: PRJNA109767 | ENA |
REPOSITORIES: ENA
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Project description:The retinoblastoma cell cycle regulator pRb and the two related proteins p107 and p130 are thought to suppress cancer development both by inhibiting the G1/S transition of the cell cycle in response to growth-arrest signals and by promoting cellular differentiation. Here, we investigated the phenotype of Rb family triple knock-out (TKO) embryonic stem cells as they differentiate in vivo and in culture. Confirming the central role of the Rb gene family in cell cycle progression, TKO mouse embryos did not survive past mid-gestation and differentiating TKO cells displayed increased proliferation and cell death. However, patterning and cell fate determination were largely unaffected in these TKO embryos. Furthermore, a number of TKO cells, including in the neural lineage, were able to exit the cell cycle in G1 and terminally differentiate. This ability of Rb family TKO cells to undergo cell cycle arrest was associated with the repression of target genes for the E2F6 transcription factor, uncovering a pRb-independent control of the G1/S transition of the cell cycle. These results show that the Rb gene family is required for proper embryonic development but is not absolutely essential to induce G1 arrest and differentiation in certain lineages. Experiment Overall Design: Genome-wide gene expression was analyzed for wild-type and TKO ESC and EB cells. Three biological replicates were isolated for wild-type ESCs, TKO ESCs, and wild-type EBs, while five biological replicates were isolated for TKO EBs.
2009-09-12 | E-GEOD-13408 | biostudies-arrayexpress
Project description:The retinoblastoma cell cycle regulator pRb and the two related proteins p107 and p130 are thought to suppress cancer development both by inhibiting the G1/S transition of the cell cycle in response to growth-arrest signals and by promoting cellular differentiation. Here, we investigated the phenotype of Rb family triple knock-out (TKO) embryonic stem cells as they differentiate in vivo and in culture. Confirming the central role of the Rb gene family in cell cycle progression, TKO mouse embryos did not survive past mid-gestation and differentiating TKO cells displayed increased proliferation and cell death. However, patterning and cell fate determination were largely unaffected in these TKO embryos. Furthermore, a number of TKO cells, including in the neural lineage, were able to exit the cell cycle in G1 and terminally differentiate. This ability of Rb family TKO cells to undergo cell cycle arrest was associated with the repression of target genes for the E2F6 transcription factor, uncovering a pRb-independent control of the G1/S transition of the cell cycle. These results show that the Rb gene family is required for proper embryonic development but is not absolutely essential to induce G1 arrest and differentiation in certain lineages.
2009-09-01 | GSE13408 | GEO
Project description:Cell cycle exit is usually enforced during terminal differentiation in various organisms and tissues. To understand how this is achieved molecularly, we exained the genome-wide profiles of chromatin accessibility and transcriptomes at normal development stages of fly wings as well as situations where we uncoupled cell cylce exit from terminal differentiation with genetic manipulations. We found that developmentally programmed, temporal changes in chromatin accessibility at a small subset of critical cell cycle genes act to enforce cell cycle exit during terminal differentiation.
2019-05-31 | GSE131981 | 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:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b-null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. During ESC differentiation, CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1), a critical regulator of stemness. In the absence of CDC14, increased UTF1 levels prevent the firing of bivalent promoters, resulting in defective induction of the transcriptional programs required for differentiation. These results suggest that mammalian CDC14 phosphatases function during the terminal exit from the cell cycle by modulating the transition from the pluripotent to the differentiated chromatin state, at least partially by controlling chromatin dynamics and transcription in a UTF1-dependent manner.
2022-10-31 | PXD030296 | Pride
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:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.
2022-10-31 | GSE196139 | GEO
Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.
2022-10-31 | GSE196137 | GEO
Project description:The retinoblastoma tumour suppressor, Rb, has two major functions. First, it represses genes whose products are required for S-phase entry and progression, thus stabilizing cells in G1. Second, Rb synergizes with factors that induce cell cycle exit and terminal differentiation. Dictyostelium lacks a G1 phase in its cell cycle but it has a retinoblastoma orthologue, rblA. Using mRNA-Seq transcriptional profiling, we show that rblA strongly represses hundreds of genes whose products are involved in S-phase and mitosis. Both S-phase and mitotic genes are expressed at a single point in late G2 and again in mid-development, near the time when cell cycling is reactivated. RblA also activates a set of genes unique to slime moulds that function in terminal differentiation. Like its mammalian counterpart, Dictyostelium RblA plays a dual role, regulating cell cycle progression and transcriptional events leading to terminal differentiation. In the absence of a G1 phase, however, RblA functions in late G2 controlling the expression of both S-phase and mitotic genes.
2012-05-18 | GSE30368 | GEO
Project description:The molecular chaperons FK506-binding proteins (Fkbps) comprise one of three families of peptidyl prolyl isomerases, which promote the transition between cis- and trans-conformations of peptidyl prolyl bonds. Mouse Fkbp family is composed of at least 15 members, but the functions of the large family in cell proliferation and differentiation remain elusive. During myoblast differentiation, the cells need to exit the cell cycle before fusion and terminal differentiation to form myotubes. The clear distinction between proliferation and differentiation provides an ideal model with which to investigate the roles of Fkbps in these two cell biological events. We found that depletion of FkbpC in mouse myoblasts delayed the exit from the cell cycle and expression of myotube-specific genes, whereas its overexpression caused opposite effects. At a mechanistic level, our study revealed a crucial function of FkbpC in Cdk4 activation during myoblast proliferation. Cdk4 undergoes conformational changes in the HSP90/Cdc37/Cdk4 complex as a prerequisite for activation through binding to CyclinD1 accompanied by phosphorylation. Our results showed that FkbpC depletion released Cdk4 from the HSP90 complex, which increased the Cdk4/CyclinD1 complex in myoblasts and sustained high levels of phosphorylated Cdk4 and Rb during differentiation. These results explain the delayed cell cycle exit and differentiation in the depleted cells. In addition, after synchronizing the cell cycle of myoblasts we found dynamic changes of the amounts of FkbpC and Cdk4 in the HSP90 complex during the G1/S transition. Knockout mice of FkbpC demonstrated delayed muscle regeneration after chemical damage, providing an in vivo evidence for the essential role of FkbpC in muscle differentiation. Collectively, our study uncovered FkbpC's critical function as a novel switch regulating the transition from proliferation to differentiation through controlling one of the central regulators of proliferation, Cdk4.
2018-11-27 | GSE109237 | GEO