scholarly journals decapentaplegic is required for arrest in G1 phase during Drosophila eye development

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 5069-5078 ◽  
Author(s):  
J. Horsfield ◽  
A. Penton ◽  
J. Secombe ◽  
F.M. Hoffman ◽  
H. Richardson
Keyword(s):  
Cell Cycle ◽  
Eye Development ◽  
Cyclin E ◽  
Posterior Part ◽  
Cyclin A ◽  
S Phase ◽  
G1 Phase ◽  
G1 Arrest ◽  
Morphogenetic Furrow ◽  
Drosophila Cell

During eye development in Drosophila, cell cycle progression is coordinated with differentiation. Prior to differentiation, cells arrest in G1 phase anterior to and within the morphogenetic furrow. We show that Decapentaplegic (Dpp), a TGF-β family member, is required to establish this G1 arrest, since Dpp-unresponsive cells located in the anterior half of the morphogenetic furrow show ectopic S phases and ectopic expression of the cell cycle regulators Cyclins A, E and B. Conversely, ubiquitous over-expression of Dpp in the eye imaginal disc transiently inhibits S phase without affecting Cyclin E or Cyclin A abundance. This Dpp-mediated inhibition of S phase occurs independently of the Cyclin A inhibitor Roughex and of the expression of Dacapo, a Cyclin E-Cdk2 inhibitor. Furthermore, Dpp-signaling genes interact genetically with a hypomorphic cyclin E allele. Taken together our results suggest that Dpp acts to induce G1 arrest in the anterior part of the morphogenetic furrow by a novel inhibitory mechanism. In addition, our results provide evidence for a Dpp-independent mechanism that acts in the posterior part of the morphogenetic furrow to maintain G1 arrest.

An expansion phase precedes terminal erythroid differentiation of hematopoietic progenitor cells from cord blood in vitro and is associated with up-regulation of cyclin E and cyclin-dependent kinase 2

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3985-3987 ◽  
Author(s):  
Mu-Shui Dai ◽  
Charlie R. Mantel ◽  
Zhen-Biao Xia ◽  
Hal E. Broxmeyer ◽  
Li Lu
Keyword(s):  
Cell Cycle ◽  
Cord Blood ◽  
Cyclin E ◽  
Erythroid Differentiation ◽  
S Phase ◽  
Cyclin D3 ◽  
G1 Phase ◽  
Cyclin Dependent Kinase ◽  
Terminal Erythroid Differentiation

The dynamics of cell cycle regulation were investigated during in vitro erythroid proliferation and differentiation of CD34+cord blood cells. An unusual cell cycle profile with a majority of cells in S phase (70.2%) and minority of cells in G1 phase (27.4%) was observed in burst-forming unit-erythrocytes (BFU-E)–derived erythroblasts from a 7-day culture of CD34+ cells stimulated with interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), Steel factor, and Epo. Terminal erythroid differentiation was accompanied by a rapid increase of G0/G1 phase cells. Expression of cyclin E and cyclin-dependent kinase 2 (cdk2) correlated with the proportion of S phase cells. Cyclin D3 was moderately up-regulated during the proliferation phase, and both cyclin E and D3 were rapidly down-regulated during terminal differentiation. This suggests that the high proliferation potential of erythroblasts is associated with temporal up-regulation of cyclin E and cdk2.

scholarly journals Inhibitory Effects of 1α,25-Dihydroxyvitamin D3 on the G1–S Phase-Controlling Machinery

2001 ◽  
Vol 15 (8) ◽  
pp. 1370-1380 ◽  
Author(s):  
Simon Skjøde Jensen ◽  
Mogens Winkel Madsen ◽  
Jiri Lukas ◽  
Lise Binderup ◽  
Jiri Bartek
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Time Course ◽  
Cancer Cell Line ◽  
Cyclin A ◽  
S Phase ◽  
Cyclin D3 ◽  
G1 Arrest ◽  
Dihydroxyvitamin D3 ◽  
Mcf 7

Abstract The nuclear hormone 1α,25-dihydroxyvitamin D3 induces cell cycle arrest, differentiation, or apoptosis depending on target cell type and state. Although the antiproliferative effect of 1α,25-dihydroxyvitamin D3 has been known for years, the molecular basis of the cell cycle blockade by 1α,25-dihydroxyvitamin D3 remains largely unknown. Here we have investigated the mechanisms underlying the G1 arrest induced upon 1α,25-dihydroxyvitamin D3 treatment of the human breast cancer cell line MCF-7. Twenty-four-hour exposure of exponentially growing MCF-7 cells to 1α,25-dihydroxyvitamin D3 impeded proliferation by preventing S phase entry, an effect that correlated with appearance of the growth-suppressing, hypophosphorylated form of the retinoblastoma protein (pRb), and modulation of cyclin-dependent kinase (cdk) activities of cdk-4, -6, and -2. Time course immunochemical and biochemical analyses of the cellular and molecular effects of 1α,25-dihydroxyvitamin D3 treatment for up to 6 d revealed a dynamic chain of events, preventing activation of cyclin D1/cdk4, and loss of cyclin D3, which collectively lead to repression of the E2F transcription factors and thus negatively affected cyclin A protein expression. While the observed 10-fold inhibition of cyclin D1/cdk 4-associated kinase activity appeared independent of cdk inhibitors, the activity of cdk 2 decreased about 20-fold, reflecting joint effects of the lower abundance of its cyclin partners and a significant increase of the cdk inhibitor p21CIP1/WAF1, which blocked the remaining cyclin A(E)/cdk 2 complexes. Together with a rapid down-modulation of the c-Myc oncoprotein in response to 1α,25-dihydroxyvitamin D3, these results demonstrate that 1α,25-dihydroxyvitamin D3 inhibits cell proliferation by targeting several key regulators governing the G1/S transition.

scholarly journals Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes.

1995 ◽  
Vol 15 (8) ◽  
pp. 4215-4224 ◽  
Author(s):  
J DeGregori ◽  
T Kowalik ◽  
J R Nevins
Keyword(s):  
Transcription Factor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Recombinant Adenovirus ◽  
Cyclin E ◽  
Cyclin A ◽  
S Phase ◽  
Nuclear Antigen ◽  
G1 Arrest ◽  
E2f1 Transcription Factor

Although a number of transfection experiments have suggested potential targets for the action of the E2F1 transcription factor, as is the case for many transcriptional regulatory proteins, the actual targets in their normal chromosomal environment have not been demonstrated. We have made use of a recombinant adenovirus containing the E2F1 cDNA to infect quiescent cells and then measure the activation of endogenous cellular genes as a consequence of E2F1 production. We find that many of the genes encoding S-phase-acting proteins previously suspected to be E2F targets, including DNA polymerase alpha, thymidylate synthase, proliferating cell nuclear antigen, and ribonucleotide reductase, are indeed induced by E2F1. Several other candidates, including the dihydrofolate reductase and thymidine kinase genes, were only minimally induced by E2F1. In addition to the S-phase genes, we also find that several genes believed to play regulatory roles in cell cycle progression, such as the cdc2, cyclin A, and B-myb genes, are also induced by E2F1. Moreover, the cyclin E gene is strongly induced by E2F1, thus defining an autoregulatory circuit since cyclin E-dependent kinase activity can stimulate E2F1 transcription, likely through the phosphorylation and inactivation of Rb and Rb family members. Finally, we also demonstrate that a G1 arrest brought about by gamma irradiation is overcome by the overexpression of E2F1 and that this coincides with the enhanced activation of key target genes, including the cyclin A and cyclin E genes.

Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 278-285 ◽  
Author(s):  
Thomas Decker ◽  
Susanne Hipp ◽  
Ingo Ringshausen ◽  
Christian Bogner ◽  
Madlene Oelsner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Cyclin A ◽  
Cyclin D3 ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Cycle Regulation

Abstract In B-cell chronic lymphocytic leukemia (B-CLL), malignant cells seem to be arrested in the G0/early G1phase of the cell cycle, and defective apoptosis might be involved in disease progression. However, increasing evidence exists that B-CLL is more than a disease consisting of slowly accumulating resting B cells: a proliferating pool of cells has been described in lymph nodes and bone marrow and might feed the accumulating pool in the blood. Rapamycin has been reported to inhibit cell cycle progression in a variety of cell types, including human B cells, and has shown activity against a broad range of human tumor cell lines. Therefore, we investigated the ability of rapamycin to block cell cycle progression in proliferating B-CLL cells. We have recently demonstrated that stimulation with CpG-oligonucleotides and interleukin-2 provides a valuable model for studying cell cycle regulation in malignant B cells. In our present study, we demonstrated that rapamycin induced cell cycle arrest in proliferating B-CLL cells and inhibited phosphorylation of p70s6 kinase (p70s6k). In contrast to previous reports on nonmalignant B cells, the expression of the cell cycle inhibitor p27 was not changed in rapamycin-treated leukemic cells. Treatment with rapamycin prevented retinoblastoma protein (RB) phosphorylation in B-CLL cells without affecting the expression of cyclin D2, but cyclin D3 was no longer detectable in rapamycin-treated B-CLL cells. In addition, rapamycin treatment inhibited cyclin-dependent kinase 2 activity by preventing up-regulation of cyclin E and cyclin A. Interestingly, survivin, which is expressed in the proliferation centers of B-CLL patients in vivo, is not up-regulated in rapamycin-treated cells. Therefore, rapamycin interferes with the expression of many critical molecules for cell cycle regulation in cycling B-CLL cells. We conclude from our study that rapamycin might be an attractive substance for therapy for B-CLL patients by inducing a G1 arrest in proliferating tumor cells.

scholarly journals A β-carboline derivative-based nickel(ii) complex as a potential antitumor agent: synthesis, characterization, and cytotoxicity

MedChemComm ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 100-107 ◽  
Author(s):  
Jing-Mei Yang ◽  
Yan-Hong Zhu ◽  
Sheng Chen ◽  
Xing Lu ◽  
Yi-Ming Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cyclin E ◽  
Antitumor Agent ◽  
Cyclin A ◽  
S Phase ◽  
Down Regulation ◽  
Cycle Arrest ◽  
Potential Antitumor

A novel nickel(ii) complex was synthesized and characterized. It significantly induced cell cycle arrest at S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27.

Phospholipase Cδ1 regulates cell proliferation and cell-cycle progression from G1- to S-phase by control of cyclin E–CDK2 activity

2008 ◽  
Vol 415 (3) ◽  
pp. 439-448 ◽  
Author(s):  
Katherine A. Kaproth-Joslin ◽  
Xiangquan Li ◽  
Sarah E. Reks ◽  
Grant G. Kelley
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Cyclin E ◽  
Critical Role ◽  
S Phase ◽  
G1 Phase ◽  
Serum Starvation ◽  
Cycle Progression ◽  
Cdk2 Activity

In the present study, we examined the role of PLCδ1 (phospholipase C δ1) in the regulation of cellular proliferation. We demonstrate that RNAi (RNA interference)-mediated knockdown of endogenous PLCδ1, but not PLCβ3 or PLCϵ, induces a proliferation defect in Rat-1 and NIH 3T3 fibroblasts. The decreased proliferation was not due to an induction of apoptosis or senescence, but was associated with an approx. 60% inhibition of [3H]thymidine incorporation. Analysis of the cell cycle with BrdU (bromodeoxyuridine)/propidium iodide-labelled FACS (fluorescence-activated cell sorting) demonstrated an accumulation of cells in G0/G1-phase and a corresponding decrease in cells in S-phase. Further examination of the cell cycle after synchronization by serum-starvation demonstrated normal movement through G1-phase but delayed entry into S-phase. Consistent with these findings, G1 cyclin (D2 and D3) and CDK4 (cyclin-dependent kinase 4) levels and associated kinase activity were not affected. However, cyclin E-associated CDK2 activity, responsible for G1-to-S-phase progression, was inhibited. This decreased activity was accompanied by unchanged CDK2 protein levels and paradoxically elevated cyclin E and cyclin E-associated CDK2 levels, suggesting inhibition of the cyclin E–CDK2 complex. This inhibition was not due to altered stimulatory or inhibitory phosphorylation of CDK2. However, p27, a Cip/Kip family CKI (CDK inhibitor)-binding partner, was elevated and showed increased association with CDK2 in PLCδ1-knockdown cells. The result of the present study demonstrate a novel and critical role for PLCδ1 in cell-cycle progression from G1-to-S-phase through regulation of cyclin E–CDK2 activity and p27 levels.

A Drosophila G1-specific cyclin E homolog exhibits different modes of expression during embryogenesis

Development ◽  
1993 ◽  
Vol 119 (3) ◽  
pp. 673-690 ◽  
Author(s):  
H.E. Richardson ◽  
L.V. O'Keefe ◽  
S.I. Reed ◽  
R. Saint
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Cyclin E ◽  
S Phase ◽  
G1 Phase ◽  
Cycle Phase ◽  
E Gene ◽  
G1 Cyclin

We have isolated a Drosophila homolog of the human G1-specific cyclin E gene. Cyclin E proteins thus constitute an evolutionarily conserved subfamily of metazoan cyclins. The Drosophila cyclin E gene, DmcycE, encodes two proteins with a common C-terminal region and unique N-terminal regions. Unlike other Drosophila cyclins, DmcycE exhibits a dynamic pattern of expression during development. DmcycE is supplied maternally, but at the completion of the cleavage divisions and prior to mitosis 14, the maternal transcripts are rapidly degraded in all cells except the pole (germ) cells. Two modes of DmcycE expression are observed in the subsequent divisions. During cycles 14, 15 and 16 in non-neural cells, DmcycE mRNA levels show no cell-cycle-associated variation. DmcycE expression in these cells is therefore independent of the cell cycle phase. In contrast, expression in proliferating embryonic peripheral nervous system cells occurs during interphase as a brief pulse that initiates before and overlaps with S phase, demonstrating the presence of a G1 phase in these embryonic neural cell cycles. DmcycE appears not to be expressed in cells that undergo endoreplication cycles during polytenization. The structural homology to human cyclin E, the ability of DmcycE to rescue a G1 cyclin-deficient yeast strain, the presence of multiple PEST sequences characteristic of G1-specific cyclins and expression during G1 phase in proliferating peripheral nervous system cells all argue that Drosophila cyclin E is a G1 cyclin. Constitutive DmcycE expression in embryonic cycles lacking a G1 phase, in contrast to expression during the G1-S phase transition in cycles exhibiting a G1 phase, implicates DmcycE expression in the regulation of the G1 to S phase transition during Drosophila embryogenesis.

An expansion phase precedes terminal erythroid differentiation of hematopoietic progenitor cells from cord blood in vitro and is associated with up-regulation of cyclin E and cyclin-dependent kinase 2

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3985-3987 ◽  
Author(s):  
Mu-Shui Dai ◽  
Charlie R. Mantel ◽  
Zhen-Biao Xia ◽  
Hal E. Broxmeyer ◽  
Li Lu
Keyword(s):  
Cell Cycle ◽  
Cord Blood ◽  
Cyclin E ◽  
Erythroid Differentiation ◽  
S Phase ◽  
Cyclin D3 ◽  
G1 Phase ◽  
Cyclin Dependent Kinase ◽  
Terminal Erythroid Differentiation

Abstract The dynamics of cell cycle regulation were investigated during in vitro erythroid proliferation and differentiation of CD34+cord blood cells. An unusual cell cycle profile with a majority of cells in S phase (70.2%) and minority of cells in G1 phase (27.4%) was observed in burst-forming unit-erythrocytes (BFU-E)–derived erythroblasts from a 7-day culture of CD34+ cells stimulated with interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), Steel factor, and Epo. Terminal erythroid differentiation was accompanied by a rapid increase of G0/G1 phase cells. Expression of cyclin E and cyclin-dependent kinase 2 (cdk2) correlated with the proportion of S phase cells. Cyclin D3 was moderately up-regulated during the proliferation phase, and both cyclin E and D3 were rapidly down-regulated during terminal differentiation. This suggests that the high proliferation potential of erythroblasts is associated with temporal up-regulation of cyclin E and cdk2.

scholarly journals Amiloride added together with bumetanide completely blocks mouse 3T3-cell exit from G0/G1-phase and entry into S-phase

1986 ◽  
Vol 239 (3) ◽  
pp. 745-750 ◽  
Author(s):  
R Panet ◽  
D Snyder ◽  
H Atlan
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Dna Synthesis ◽  
Serum Insulin ◽  
S Phase ◽  
G1 Phase ◽  
G1 Arrest ◽  
Inhibitory Effects ◽  
Cell Transition ◽  
Mitogenic Signal

In this study we tested the hypothesis that stimulation of univalent-cation fluxes which follow the addition of growth factors are required for cell transition through the G1-phase of the cell cycle. The effect of two drugs, amiloride and bumetanide, were tested on exit of BALB/c 3T3 cells from G0/G1-phase and entry into S-phase (DNA synthesis). Amiloride, an inhibitor of the Na+/H+ antiport, only partially inhibited DNA synthesis induced by serum. Bumetanide, an inhibitor of the Na+/K+ co-transport, only slightly suppressed DNA synthesis by itself, but when added together with amiloride completely blocked cell transition through G1 and entry into S-phase. Similar inhibitory effects of the two drugs were found on the induction of ornithine decarboxylase (ODC) (a marker of mid-G1-phase) in synchronized cells stimulated by either partially purified fibroblast growth factor (FGF) or serum. To test this hypothesis further, cells arrested in G0/G1 were stimulated by serum, insulin or FGF. All induced similar elevations of cellular K+ content during the early G1-phase of the cell cycle. However, serum and FGF, but not insulin, released the cells from the G0/G1 arrest, as measured by ODC enzyme induction. This result implies that the increase in cellular K+ content may be necessary but not sufficient for induction of early events during the G1-phase. The synergistic inhibitory effects of amiloride and bumetanide on the two activities stimulated by serum growth factors, namely ODC induction (mid-G1) and thymidine incorporation into DNA (S-phase), suggested that the amiloride-sensitive Na+/H+ antiport system together with the bumetanide-sensitive Na+/K+ transporter play a role in the mitogenic signal.

scholarly journals Ectopic expression of cyclin D1 but not cyclin E induces anchorage-independent cell cycle progression.

1997 ◽  
Vol 17 (9) ◽  
pp. 5640-5647 ◽  
Author(s):  
D Resnitzky
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Kinase Activity ◽  
Cyclin E ◽  
Ectopic Expression ◽  
S Phase ◽  
G1 Arrest ◽  
Independent Manner ◽  
Cycle Progression

Normal fibroblasts are dependent on adhesion to a substrate for cell cycle progression. Adhesion-deprived Rat1 cells arrest in the G1 phase of the cell cycle, with low cyclin E-dependent kinase activity, low levels of cyclin D1 protein, and high levels of the cyclin-dependent kinase inhibitor p27kip1. To understand the signal transduction pathway underlying adhesion-dependent growth, it is important to know whether prevention of any one of these down-regulation events under conditions of adhesion deprivation is sufficient to prevent the G1 arrest. To that end, sublines of Rat1 fibroblasts capable of expressing cyclin E, cyclin D1, or both in an inducible manner were used. Ectopic expression of cyclin D1 was sufficient to allow cells to enter S phase in an adhesion-independent manner. In contrast, cells expressing exogenous cyclin E at a level high enough to overcome the p27kip1-imposed inhibition of cyclin E-dependent kinase activity still arrested in G1 when deprived of adhesion. Moreover, expression of both cyclins D1 and E in the same cells did not confer any additional growth advantage upon adhesion deprivation compared to the expression of cyclin D1 alone. Exogenously expressed cyclin D1 was down-regulated under conditions of adhesion deprivation, despite the fact that it was expressed from a heterologous promoter. The ability of cyclin D1-induced cells to enter S phase in an adhesion-independent manner disappears as soon as cyclin D1 proteins disappear. These results suggest that adhesion-dependent cell cycle progression is mediated through cyclin D1, at least in Rat1 fibroblasts.

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