TRANSCRIPTIONAL CONTROL OF CELL CYCLE PROGRESSION: THE HISTONE GENE IS A PARADIGM FOR THE G1/S PHASE AND PROLIFERATION/DIFFERENTIATION TRANSITIONS

1996 ◽  
Vol 20 (1) ◽  
pp. 41-49 ◽  
Author(s):  
G STEIN
Keyword(s):  
Cell Cycle ◽  
Transcriptional Control ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Histone Gene ◽  
Cycle Progression

scholarly journals NPAT Expression Is Regulated by E2F and Is Essential for Cell Cycle Progression

2003 ◽  
Vol 23 (8) ◽  
pp. 2821-2833 ◽  
Author(s):  
Guang Gao ◽  
Adrian P. Bracken ◽  
Karina Burkard ◽  
Diego Pasini ◽  
Marie Classon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Histone Gene ◽  
Cycle Progression ◽  
Histone Gene Transcription ◽  
E2f Proteins ◽  
Phase Entry

ABSTRACT NPAT is an in vivo substrate of cyclin E-Cdk2 kinase and is thought to play a critical role in coordinated transcriptional activation of histone genes during the G1/S-phase transition and in S-phase entry in mammalian cells. Here we show that NPAT transcription is up-regulated at the G1/S-phase boundary in growth-stimulated cells and that the NPAT promoter responds to activation by E2F proteins. We demonstrate that endogenous E2F proteins interact with the promoter of the NPAT gene in vivo and that induced expression of E2F1 stimulates NPAT mRNA expression, supporting the idea that the expression of NPAT is regulated by E2F. Consistently, we find that the E2F sites in the NPAT promoter are required for its activation during the G1/S-phase transition. Moreover, we show that the expression of NPAT accelerates S-phase entry in cells released from quiescence. The inhibition of NPAT expression by small interfering RNA duplexes impedes cell cycle progression and histone gene expression in tissue culture cells. Thus, NPAT is an important E2F target that is required for cell cycle progression in mammalian cells. As NPAT is involved in the regulation of S-phase-specific histone gene transcription, our findings indicate that NPAT links E2F to the activation of S-phase-specific histone gene transcription.

scholarly journals Context dependent roles for RB-E2F transcriptional regulation in tumor suppression

2018 ◽  
Author(s):  
Michael J. Thwaites ◽  
Matthew J. Cecchini ◽  
Daniel T. Passos ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Transcriptional Control ◽  
Cell Cycle Progression ◽  
Cancer Susceptibility ◽  
S Phase ◽  
Mouse Strains ◽  
Cell Cycle Exit ◽  
Cycle Progression ◽  
Cell Cycle Genes ◽  
Primary Fibroblasts

AbstractRB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer. Based on this background we sought to probe the vulnerabilities of RB-E2F transcriptional control defects found in Rb1R461E,K542E mutant mice (Rb1G) through genetic crosses with other mouse strains. We generated Rb1G/G mice in combination with Trp53 and Cdkn1a deficiencies, as well as in combination with KrasG12D. The Rb1G mutation enhanced Trp53 cancer susceptibility, but had no effect in combination with Cdkn1a deficiency or KrasG12D. Collectively, this study indicates that compromised RB-E2F transcriptional control is not uniformly cancer enabling, but rather has potent oncogenic effects when combined with specific vulnerabilities.

scholarly journals ANKHD1 Is Required for S Phase Progression and Histone Gene Transcription in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2002-2002
Author(s):  
Anamika Dhyani ◽  
Patricia Favro ◽  
Sara T O Saad
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Gene Transcription ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Histone Gene ◽  
Cycle Progression ◽  
Promoter Sequences ◽  
Core Histones ◽  
Histone Gene Transcription

Abstract Background ANKHD1, Ankyrin repeat and KH domain-containing protein 1 is highly expressed in CD138+ cells of patients with multiple myeloma (MM) as well as in MM cell lines (U266, RPMI 8226 ,MM1S and MM1R. Our microarray studies showed modulation of several histone variants after ANKHD1 silencing (not published). Furthermore ANKHD1 silencing in MM cell lines resulted in S phase arrest (1). As genes involved in histone transcription are upregulated in S phase, and ANKHD1 downregulation inhibits cell cycle progression at S phase, we hypothesized that ANKHD1 might be a protein that gets upregulated in S phase and plays a role in histone gene transcription. Hence, in the present study ANKHD1 expression was sought at different phases of cell cycle and a possible interaction of ANKHD1 with histones was also investigated, in addition to the effect of ANKHD1 downregulation on histone expression in a MM cell line. Methods MM cell line U266 was synchronized at G1 phase by serum starvation (16h), S phase by double thymidine block (2mM) followed by release in 24 μM deoxycytidine (4h) or G2 phase by nocodazole treatment(50ng/ml;16h). Cells were stained with PI and analyzed by flow cytometry for DNA content. Percentage of cells in G1, S, or G2/M was calculated using the ModFit program. Western blot was then carried out for ANKHD1 expression in U266 cells untreated or synchronized at different G1, S and G2 phases of cell cycle. ANKHD1 expression was inhibited by lentiviral mediated ANKHD1shRNA transduction and its effect on expression of histones was studied by qPCR and immunoblot. Further chromatin immunoprecipitation (ChIP) assay was performed to study the interaction between ANKHD1 and histones using EZ-Magna ChIP™ A kit(Millipore) followed by qPCR with primers specific to core histones promoter region. Immunofluorescence was performed to determine the localization of ANKHD1 before and after leptomycin B treatment of U266 cells. Results. In the present study, endogenous ANKHD1 expression showed a clear cell-cycle-dependence, peaking during S phase, when cells were synchronized by double thymidine block followed by deoxycytidine release. Further down-regulation of ANKHD1 expression in U266 cells by lentiviral mediated shRNA against ANKHD1 resulted in a significant reduction of histones (p<0.05) at both mRNA and protein levels. Chromatin immunoprecipitation followed by qPCR with primers specific to core histones promoter region showed that ANKHD1, though not IgG (negative control) coprecipitated with histone gene chromatin, thus confirming the interaction between the core histone promoter regions and ANKHD1. Fold enrichment (mean ± sd) of promoter sequences bound to ANKHD1 were 7.74 ± 0.048, 7.78± 0.129 and 7.06± 0.178 for histones H2B/r, H3/c and H4/e, respectively. Immunofluorescence after leptomycin B treatment (20ng/ml) of U266 wild type cells for 24 hours showed accumulation of ANKHD1 inside nucleus as compared to untreated cells where ANKHD1 was found to be predominantly in cytoplasm. This suggests transport of ANKHD1 between nucleus and cytoplasm. Conclusion ANKHD1 expression peaks during S phase of cell cycle and downregulation of ANKHD1 protein by shRNA results in downregulation of histones. ANKHD1 interacts with histone gene promoter sequences and modulates histones transcription. These results suggest that ANKHD1 might be an important component of the machinery required for histone mRNA expression and cell-cycle progression. Furthermore, ANKHD1 protein which was earlier reported to be localized predominantly in cytoplasm (1) is herein suggested to shuttle between cytoplasm and nucleus thereby playing a role in gene regulation. Extensive studies are required to understand the mechanism underlying the regulation of gene transcription by ANKHD1. References: 1) ANKHD1 regulates cell cycle progression and proliferation in multiple myeloma cells. Dhyani et al. FEBS letters 2012. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Meiosis-Specific Crs1 Cyclin Is Required for Efficient S-Phase Progression and Stable Nuclear Architecture

2021 ◽  
Vol 22 (11) ◽  
pp. 5483
Author(s):  
Luisa F. Bustamante-Jaramillo ◽  
Celia Ramos ◽  
Cristina Martín-Castellanos
Keyword(s):  
Cell Cycle ◽  
Translational Control ◽  
Cell Cycle Progression ◽  
Nuclear Architecture ◽  
Strand Break ◽  
Spindle Pole ◽  
S Phase ◽  
Cycle Progression ◽  
Single Wave ◽  
Phase Progression

Cyclins and CDKs (Cyclin Dependent Kinases) are key players in the biology of eukaryotic cells, representing hubs for the orchestration of physiological conditions with cell cycle progression. Furthermore, as in the case of meiosis, cyclins and CDKs have acquired novel functions unrelated to this primal role in driving the division cycle. Meiosis is a specialized developmental program that ensures proper propagation of the genetic information to the next generation by the production of gametes with accurate chromosome content, and meiosis-specific cyclins are widespread in evolution. We have explored the diversification of CDK functions studying the meiosis-specific Crs1 cyclin in fission yeast. In addition to the reported role in DSB (Double Strand Break) formation, this cyclin is required for meiotic S-phase progression, a canonical role, and to maintain the architecture of the meiotic chromosomes. Crs1 localizes at the SPB (Spindle Pole Body) and is required to stabilize the cluster of telomeres at this location (bouquet configuration), as well as for normal SPB motion. In addition, Crs1 exhibits CDK(Cdc2)-dependent kinase activity in a biphasic manner during meiosis, in contrast to a single wave of protein expression, suggesting a post-translational control of its activity. Thus, Crs1 displays multiple functions, acting both in cell cycle progression and in several key meiosis-specific events.

scholarly journals Spirulina Crude Protein Promotes the Migration and Proliferation in IEC-6 Cells by Activating EGFR/MAPK Signaling Pathway

Marine Drugs ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 205
Author(s):  
Su-Jin Jeong ◽  
Jeong-Wook Choi ◽  
Min-Kyeong Lee ◽  
Youn-Hee Choi ◽  
Taek-Jeong Nam
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
Crude Protein ◽  
Cell Cycle Progression ◽  
Intestinal Epithelial Cells ◽  
Mapk Signaling ◽  
S Phase ◽  
Intestinal Epithelial ◽  
Cycle Progression

Spirulina is a type of filamentous blue-green microalgae known to be rich in nutrients and to have pharmacological effects, but the effect of spirulina on the small intestine epithelium is not well understood. Therefore, this study aims to investigate the proliferative effects of spirulina crude protein (SPCP) on a rat intestinal epithelial cells IEC-6 to elucidate the mechanisms underlying its effect. First, the results of wound-healing and cell viability assays demonstrated that SPCP promoted migration and proliferation in a dose-dependent manner. Subsequently, when the mechanisms of migration and proliferation promotion by SPCP were confirmed, we found that the epidermal growth factor receptor (EGFR) and mitogen-activated protein (MAPK) signaling pathways were activated by phosphorylation. Cell cycle progression from G0/G1 to S phase was also promoted by SPCP through upregulation of the expression levels of cyclins and cyclin-dependent kinases (Cdks), which regulate cell cycle progression to the S phase. Meanwhile, the expression of cyclin-dependent kinase inhibitors (CKIs), such as p21 and p27, decreased with SPCP. In conclusion, our results indicate that activation of EGFR and its downstream signaling pathway by SPCP treatment regulates cell cycle progression. Therefore, these results contribute to the research on the molecular mechanism for SPCP promoting the migration and proliferation of rat intestinal epithelial cells.

SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 723-735 ◽  
Author(s):  
Hedia Chagraoui ◽  
Mira Kassouf ◽  
Sreemoti Banerjee ◽  
Nicolas Goardon ◽  
Kevin Clark ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Control ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Loss Of Function ◽  
Cycle Progression ◽  
Cell Cycle Regulator ◽  
Nuclear Changes ◽  
Cytoplasmic Maturation

Abstract Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.

scholarly journals Cubic Membranes Formation in Synchronized Human Hepatocellular Carcinoma Cells Reveals a Possible Role as a Structural Antioxidant Defense System in Cell Cycle Progression

2020 ◽  
Vol 8 ◽  
Author(s):  
Deqin Kong ◽  
Rui Liu ◽  
Jiangzheng Liu ◽  
Qingbiao Zhou ◽  
Jiaxin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Carcinoma Cells ◽  
Human Hepatocellular Carcinoma ◽  
Cycle Progression ◽  
Hepatocellular Carcinoma Cells ◽  
G2 Phase ◽  
Human Hepatocellular Carcinoma Cells

Cubic membranes (CMs) represent unique biological membrane structures with highly curved three-dimensional periodic minimal surfaces, which have been observed in a wide range of cell types and organelles under various stress conditions (e. g., starvation, virus-infection, and oxidation). However, there are few reports on the biological roles of CMs, especially their roles in cell cycle. Hence, we established a stable cell population of human hepatocellular carcinoma cells (HepG2) of 100% S phase by thymidine treatment, and determined certain parameters in G2 phase released from S phase. Then we found a close relationship between CMs formation and cell cycle, and an increase in reactive oxygen species (ROS) and mitochondrial function. After the synchronization of HepG2 cells were induced, CMs were observed through transmission electron microscope in G2 phase but not in G1, S and M phase. Moreover, the increased ATP production, mitochondrial and intracellular ROS levels were also present in G2 phase, which demonstrated a positive correlation with CMs formation by Pearson correlation analysis. This study suggests that CMs may act as an antioxidant structure in response to mitochondria-derived ROS during G2 phase and thus participate in cell cycle progression.

scholarly journals Effects of Guanine Nucleotide Depletion on Cell Cycle Progression in Human T Lymphocytes

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2896-2904 ◽  
Author(s):  
Josée Laliberté ◽  
Ann Yee ◽  
Yue Xiong ◽  
Beverly S. Mitchell
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Lymphocytes ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Guanine Nucleotides ◽  
Erythroid Cell ◽  
Guanine Nucleotide ◽  
Cycle Progression ◽  
Human T Lymphocytes

Depletion of guanine nucleotide pools after inhibition of inosine monophosphate dehydrogenase (IMPDH) potently inhibits DNA synthesis by arresting cells in G1 and has been shown to induce the differentiation of cultured myeloid and erythroid cell lines, as well as chronic granulocytic leukemic cells after blast transformation. Inhibitors of IMPDH are also highly effective as immunosuppressive agents. The mechanism underlying these pleiotropic effects of depletion of guanine nucleotides is unknown. We have examined the effects of mycophenolic acid (MPA), a potent IMPDH inhibitor, on the cell cycle progression of activated normal human T lymphocytes. MPA treatment resulted in the inhibition of pRb phosphorylation and cell entry into S phase. The expression of cyclin D3, a major component of the cyclin-dependent kinase (CDK) activity required for pRb phosphorylation, was completely abrogated by MPA treatment of T cells activated by interleukin-2 (IL-2) and leucoagglutinin (PHA-L), whereas the expression of cyclin D2, CDK6, and CDK4 was more mildly attenuated. The direct kinase activity of a complex immunoprecipitated with anti-CDK6 antibody was also inhibited. In addition, MPA prevented the IL-2–induced elimination of p27Kip1, a CDK inhibitor, and resulted in the retention of high levels of p27Kip1 in IL-2/PHA-L–treated T cells bound to CDK2. These results indicate that inhibition of the de novo synthesis of guanine nucleotides blocks the transition of normal peripheral blood T lymphocytes from G0 to S phase in early- to mid-G1 and that this cell cycle arrest results from inhibition of the induction of cyclin D/CDK6 kinase and the elimination of p27Kip1 inhibitory activity.

scholarly journals Cellular Ras and Cyclin D1 Are Required during Different Cell Cycle Periods in Cycling NIH 3T3 Cells

1999 ◽  
Vol 19 (7) ◽  
pp. 4623-4632 ◽  
Author(s):  
Masahiro Hitomi ◽  
Dennis W. Stacey
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Time Lapse ◽  
S Phase ◽  
3T3 Cells ◽  
Cycle Progression ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT Novel techniques were used to determine when in the cell cycle of proliferating NIH 3T3 cells cellular Ras and cyclin D1 are required. For comparison, in quiescent cells, all four of the inhibitors of cell cycle progression tested (anti-Ras, anti-cyclin D1, serum removal, and cycloheximide) became ineffective at essentially the same point in G1 phase, approximately 4 h prior to the beginning of DNA synthesis. To extend these studies to cycling cells, a time-lapse approach was used to determine the approximate cell cycle position of individual cells in an asynchronous culture at the time of inhibitor treatment and then to determine the effects of the inhibitor upon recipient cells. With this approach, anti-Ras antibody efficiently inhibited entry into S phase only when introduced into cells prior to the preceding mitosis, several hours before the beginning of S phase. Anti-cyclin D1, on the other hand, was an efficient inhibitor when introduced up until just before the initiation of DNA synthesis. Cycloheximide treatment, like anti-cyclin D1 microinjection, was inhibitory throughout G1 phase (which lasts a total of 4 to 5 h in these cells). Finally, serum removal blocked entry into S phase only during the first hour following mitosis. Kinetic analysis and a novel dual-labeling technique were used to confirm the differences in cell cycle requirements for Ras, cyclin D1, and cycloheximide. These studies demonstrate a fundamental difference in mitogenic signal transduction between quiescent and cycling NIH 3T3 cells and reveal a sequence of signaling events required for cell cycle progression in proliferating NIH 3T3 cells.

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