scholarly journals Ellagic Acid Reduces Adipogenesis through Inhibition of Differentiation-Prevention of the Induction of Rb Phosphorylation in 3T3-L1 Adipocytes

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Lifeng Wang ◽  
Linlin Li ◽  
Xinjian Ran ◽  
Mei Long ◽  
Minfang Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Ellagic Acid ◽  
Cyclin A ◽  
Underlying Mechanism ◽  
S Phase ◽  
Binding Ability ◽  
Associated Proteins ◽  
Rb Phosphorylation ◽  
Inhibition Of Differentiation

Ellagic acid (EA) present in many fruits and nuts serves as antiproliferation, anti-inflammatory, and antitumorigenic properties. However, the effect of EA on preadipocytes adipogenesis and its mechanism(s) have not been elucidated. The present study was designed to examine the effect of EA on adipogenesis in 3T3-L1 preadipocytes and underlying mechanism(s) of action involved. Data show that EA administration decreased the accumulation of lipid droplets. The inhibition was diminished when the addition of EA was delayed to days 2–4 of differentiation. Clonal expansion was reduced in the presence of EA. FACS analysis showed that EA blocked the cell cycle at the G1/S transition. EdU incorporation also confirmed that EA refrained cell from entering S phase. Our data also revealed that the differentiation-induced protein expression of Cyclin A and phosphorylation of the retinoblastoma protein (Rb) were impaired by EA. Differentiation-dependent expression and DNA-binding ability of C/EBPαwere also inhibited by EA. Alterations in cell cycle-associated proteins may be important with respect to the antiadipogenic action of EA. In conclusion, EA is capable of inhibiting adipogenesis in 3T3-L1 adipocytes possibly through reduction of Cyclin A protein expression and Rb phosphorylation. With the blocking of G1/S phase transition, EA suppresses terminal differentiation and lipid accumulation in 3T3-L1 adipocytes.

mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators

2005 ◽  
Vol 289 (6) ◽  
pp. C1457-C1465 ◽  
Author(s):  
Gustavo A. Nader ◽  
Thomas J. McLoughlin ◽  
Karyn A. Esser
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Cyclin D1 ◽  
Ribosomal Rna ◽  
Molecular Mechanisms ◽  
D1 Protein ◽  
Rna Content ◽  
Cyclin D1 Protein ◽  
Rb Phosphorylation ◽  
Myotube Hypertrophy

The purpose of this study was to identify the potential downstream functions associated with mammalian target of rapamycin (mTOR) signaling during myotube hypertrophy. Terminally differentiated myotubes were serum stimulated for 3, 6, 12, 24, and 48 h. This treatment resulted in significant myotube hypertrophy (protein/DNA) and increased RNA content (RNA/DNA) with no changes in DNA content or indices of cell proliferation. During myotube hypertrophy, the increase in RNA content was accompanied by an increase in tumor suppressor protein retinoblastoma (Rb) phosphorylation and a corresponding increase in the availability of the ribosomal DNA transcription factor upstream binding factor (UBF). Serum stimulation also induced an increase in cyclin D1 protein expression in the differentiated myotubes with a concomitant increase in cyclin D1-dependent cyclin-dependent kinase (CDK)-4 activity toward Rb. The increases in myotube hypertrophy and RNA content were blocked by rapamycin treatment, which also prevented the increase in cyclin D1 protein expression, CDK-4 activity, Rb phosphorylation, and the increase in UBF availability. Our findings demonstrate that activation of mTOR is necessary for myotube hypertrophy and suggest that the role of mTOR is in part to modulate cyclin D1-dependent CDK-4 activity in the regulation of Rb and ribosomal RNA synthesis. On the basis of these results, we propose that common molecular mechanisms contribute to the regulation of myotube hypertrophy and growth during the G1 phase of the cell cycle.

Association of the human papillomavirus type 16 E7 protein with the S-phase-specific E2F-cyclin A complex

1993 ◽  
Vol 13 (10) ◽  
pp. 6537-6546 ◽  
Author(s):  
M Arroyo ◽  
S Bagchi ◽  
P Raychaudhuri
Keyword(s):  
Cell Cycle ◽  
Human Papillomavirus ◽  
Simian Virus 40 ◽  
Cyclin A ◽  
T Antigen ◽  
S Phase ◽  
Cellular Proteins ◽  
Hpv 16 ◽  
Adenovirus E1a ◽  
Cell Extracts

The transcription factor E2F has been shown to be involved in the expression of several cell cycle-regulated genes, and the activity of this factor is controlled by cellular proteins such as pRB and p107. E2F is also a target of the DNA virus oncoproteins (adenovirus E1A, simian virus 40 T antigen, and human papillomavirus [HPV] E7) (see the review by J. R. Nevins [Science 258: 424-429, 1992]). These viral oncoproteins dissociate an inactive complex between E2F and the retinoblastoma tumor suppressor protein (pRB), and this dissociation of the E2F-pRB complex correlates with a stimulation of the E2F-dependent transcription. In the S phase of the cell cycle, E2F forms a complex with p107, cyclin A, and the cdk2 kinase (E2F-cyclin A complex). The cellular function of this S-phase-specific complex is unclear. The adenovirus E1A protein dissociates the E2F-cyclin A complex. The HPV type 16 (HPV-16) E7 protein, which possesses significant sequence homology with E1A, does not dissociate the E2F-cyclin A complex. We find that the HPV-16 E7 protein associates very efficiently with the E2F-cyclin A complex. This association is dependent on the sequences that are also necessary for the transforming activity of E7. Moreover, the E7 protein of a low-risk HPV (type 6b) is much less efficient in binding to the E2F-cyclin A complex compared with that of the high-risk type. We also find that the E2F-cyclin A complex remains endogenously associated with the E7 protein in extracts of Caski cells, which express high levels of HPV-16 E7 protein. Finally, we have extensively purified the E2F-cyclin A complex from mouse L-cell extracts and show that, in cell extracts, the E2F-cyclin A complex remains associated with other cellular proteins.

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 C/EBPα Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

1999 ◽  
Vol 19 (4) ◽  
pp. 2936-2945 ◽  
Author(s):  
Nikolai A. Timchenko ◽  
Margie Wilde ◽  
Gretchen J. Darlington
Keyword(s):  
Cell Cycle ◽  
Knockout Mice ◽  
Cyclin A ◽  
S Phase ◽  
Hepatocyte Proliferation ◽  
Nuclear Antigen ◽  
Liver Development ◽  
Wild Type ◽  
Newborn Mice ◽  
Newborn Animals

ABSTRACT We previously showed that the rate of hepatocyte proliferation in livers from newborn C/EBPα knockout mice was increased. An examination of cell cycle-related proteins showed that the cyclin-dependent kinase (CDK) inhibitor p21 level was reduced in the knockout animals compared to that in wild-type littermates. Here we show additional cell cycle-associated proteins that are affected by C/EBPα. We have observed that C/EBPα controls the composition of E2F complexes through interaction with the retinoblastoma (Rb)-like protein, p107, during prenatal liver development. S-phase-specific E2F complexes containing E2F, DP, cdk2, cyclin A, and p107 are observed in the developing liver. In wild-type animals these complexes disappear by day 18 of gestation and are no longer present in the newborn animals. In the C/EBPα mutant, the S-phase-specific complexes do not diminish and persist to birth. The elevation of levels of the S-phase-specific E2F-p107 complexes in C/EBPα knockout mice correlates with the increased expression of several E2F-dependent genes such as those that encode cyclin A, proliferating cell nuclear antigen, and p107. The C/EBPα-mediated regulation of E2F binding is specific, since the deletion of another C/EBP family member, C/EBPβ, does not change the pattern of E2F binding during prenatal liver development. The addition of bacterially expressed, purified His-C/EBPα to the E2F binding reaction resulted in the disruption of E2F complexes containing p107 in nuclear extracts from C/EBPα knockout mouse livers. Ectopic expression of C/EBPα in cultured cells also leads to a reduction of E2F complexes containing Rb family proteins. Coimmunoprecipitation analyses revealed an interaction of C/EBPα with p107 but none with cdk2, E2F1, or cyclin A. A region of C/EBPα that has sequence similarity to E2F is sufficient for the disruption of the E2F-p107 complexes. Despite its role as a DNA binding protein, C/EBPα brings about a change in E2F complex composition through a protein-protein interaction. The disruption of E2F-p107 complexes correlates with C/EBPα-mediated growth arrest of hepatocytes in newborn animals.

scholarly journals Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM.

1995 ◽  
Vol 15 (6) ◽  
pp. 3301-3309 ◽  
Author(s):  
C Desdouets ◽  
G Matesic ◽  
C A Molina ◽  
N S Foulkes ◽  
P Sassone-Corsi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cyclic Amp ◽  
Transcription Initiation ◽  
Mammalian Cells ◽  
Binding Proteins ◽  
Regulatory Protein ◽  
Cyclin A ◽  
S Phase ◽  
Signalling Pathway

Cyclin A is a pivotal regulatory protein which, in mammalian cells, is involved in the S phase of the cell cycle. Transcription of the human cyclin A gene is cell cycle regulated. We have investigated the role of the cyclic AMP (cAMP)-dependent signalling pathway in this cell cycle-dependent control. In human diploid fibroblasts (Hs 27), induction of cyclin A gene expression at G1/S is stimulated by 8-bromo-cAMP and suppressed by the protein kinase A inhibitor H89, which was found to delay S phase entry. Transfection experiments showed that the cyclin A promoter is inducible by activation of the adenylyl cyclase signalling pathway. Stimulation is mediated predominantly via a cAMP response element (CRE) located at positions -80 to -73 with respect to the transcription initiation site and is able to bind CRE-binding proteins and CRE modulators. Moreover, activation by phosphorylation of the activators CRE-binding proteins and CRE modulator tau and levels of the inducible cAMP early repressor are cell cycle regulated, which is consistent with the pattern of cyclin A inducibility by cAMP during the cell cycle. These results suggest that the CRE is, at least partly, implicated in stimulation of cyclin A transcription at G1/S.

scholarly journals Chk1 Phosphorylates Cdh1 to Promote SCFβTRCP-Dependent Degradation of Cdh1 During S-Phase

2019 ◽  
Author(s):  
Debjani Pal ◽  
Adrian E. Torres ◽  
Abbey L. Messina ◽  
Andrew Dickson ◽  
Kuntal De ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Feedback Loop ◽  
Cellular Proliferation ◽  
Genomic Stability ◽  
Cyclin A ◽  
S Phase ◽  
Anaphase Promoting Complex ◽  
Replication Machinery ◽  
Key Factor ◽  
Phase Entry

ABSTRACTThe interplay of the Anaphase-Promoting Complex/Cyclosome (APC/C) and Skp1-Cul1-F-box (SCF) E3 ubiquitin ligases is necessary for controlling cell cycle transitions and checkpoint responses, which are critical for maintaining genomic stability. Yet, the mechanisms underlying the coordinated activity of these enzymes are not completely understood. Recently, Cyclin A- and Plk1- mediated phosphorylation of Cdh1 was demonstrated to trigger its ubiquitination by SCFβTRCP at the G1/S transition. However, Cyclin A-Cdk and Plk1 activities peak in G2 so it is unclear why Cdh1 is targeted at G1/S but not in G2. Here, we show that phosphorylation of Cdh1 by Chk1 contributes to its recognition by SCFβTRCP, promotes efficient S-phase entry, and is important for cellular proliferation. Conversely, Chk1 activity in G2 inhibits Cdh1 accumulation. Overall, these data suggest a model whereby the rise and fall of Chk1 activity is a key factor in the feedback loop between APC/CCdh1 and the replication machinery that enhances the G1/S and S/G2 transitions, respectively.

scholarly journals Cell Cycle Dysregulation by Human Cytomegalovirus: Influence of the Cell Cycle Phase at the Time of Infection and Effects on Cyclin Transcription

1998 ◽  
Vol 72 (5) ◽  
pp. 3729-3741 ◽  
Author(s):  
Bryan S. Salvant ◽  
Elizabeth A. Fortunato ◽  
Deborah H. Spector
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Cell Cycle Progression ◽  
Hcmv Infection ◽  
Cyclin A ◽  
S Phase ◽  
Cyclin B ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Time Of Infection

ABSTRACT Human cytomegalovirus (HCMV) infection inhibits cell cycle progression and alters the expression of cyclins E, A, and B (F. M. Jault, J.-M. Jault, F. Ruchti, E. A. Fortunato, C. Clark, J. Corbeil, D. D. Richman, and D. H. Spector, J. Virol. 69:6697–6704, 1995). In this study, we examined cell cycle progression, cyclin gene expression, and early viral events when the infection was initiated at different points in the cell cycle (G0, G1, and S). In all cases, infection led to cell cycle arrest. Cells infected in G0 or G1phase also showed a complete or partial absence, respectively, of cellular DNA synthesis at a time when DNA synthesis occurred in the corresponding mock-infected cells. In contrast, when cells were infected near or during S phase, many cells were able to pass through S phase and undergo mitosis prior to cell cycle arrest. S-phase infection also produced a delay in the appearance of the viral cytopathic effect and in the synthesis of immediate-early and early proteins. Labeling of cells with bromodeoxyuridine immediately prior to HCMV infection in S phase revealed that viral protein expression occurred primarily in cells which were not engaged in DNA synthesis at the time of infection. The viral-mediated induction of cyclin E, maintenance of cyclin-B protein levels, and inhibitory effects on the accumulation of cyclin A were not significantly affected when infection occurred during different phases of the cell cycle (G0, G1, and S). However, there was a delay in the observed inhibition of cyclin A in cells infected during S phase. This finding was in accord with the pattern of cell cycle progression and delay in viral gene expression associated with S-phase infection. Analysis of the mRNA revealed that the effects of the virus on cyclin E and cyclin A, but not on cyclin B, were primarily at the transcriptional level.

scholarly journals Intrinsic S phase checkpoint enforced by an antiproliferative oncosuppressor cytokine

2021 ◽  
Author(s):  
Livio Mallucci ◽  
Valerie Wells
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Self Regulation ◽  
Cyclin A ◽  
S Phase ◽  
Cycle Phase ◽  
Control Mechanisms ◽  
Checkpoint Control ◽  
Normal Cells ◽  
Orderly Transition

AbstractThe cell cycle is strictly programmed with control mechanisms that dictate order in cell cycle progression to ensure faithful DNA replication, whose deviance may lead to cancer. Checkpoint control at the G1/S, S/G2 and G2/M portals have been defined but no statutory time-programmed control for securing orderly transition through S phase has so far been identified. Here we report that in normal cells DNA synthesis is controlled by a checkpoint sited within the early part of S phase, enforced by the βGBP cytokine an antiproliferative molecule otherwise known for its oncosuppressor properties that normal cells constitutively produce for self-regulation. Suppression of active Ras and active MAPK, block of cyclin A gene expression and suppression of CDK2-cyclin A activity are events which while specific to the control of a cell cycle phase in normal cells are part of the apoptotic network in cancer cells.

scholarly journals A Protein Encoded by the Latency-Related Gene of Bovine Herpesvirus 1 Is Expressed in Trigeminal Ganglionic Neurons of Latently Infected Cattle and Interacts with Cyclin-Dependent Kinase 2 during Productive Infection

1998 ◽  
Vol 72 (10) ◽  
pp. 8133-8142 ◽  
Author(s):  
Yunquan Jiang ◽  
Ashfaque Hossain ◽  
Maria Teresa Winkler ◽  
Todd Holt ◽  
Alan Doster ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Acute Infection ◽  
Cyclin A ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Bovine Herpesvirus 1 ◽  
Cycle Progression ◽  
Latently Infected ◽  
Herpesvirus 1

ABSTRACT Despite productive viral gene expression in the peripheral nervous system during acute infection, the bovine herpesvirus 1 (BHV-1) infection cycle is blocked in sensory ganglionic neurons and consequently latency is established. The only abundant viral transcript expressed during latency is the latency-related (LR) RNA. LR gene products inhibit S-phase entry, and binding of the LR protein (LRP) to cyclin A was hypothesized to block cell cycle progression. This study demonstrates LRP is a nuclear protein which is expressed in neurons of latently infected cattle. Affinity chromatography indicated that LRP interacts with cyclin-dependent kinase 2 (cdk2)-cyclin complexes or cdc2-cyclin complexes in transfected human cells or infected bovine cells. After partial purification using three different columns (DEAE-Sepharose, Econo S, and heparin-agarose), LRP was primarily associated with cdk2-cyclin E complexes, an enzyme which is necessary for G1-to-S-phase cell cycle progression. During acute infection of trigeminal ganglia or following dexamethasone-induced reactivation, BHV-1 induces expression of cyclin A in neurons (L. M. Schang, A. Hossain, and C. Jones, J. Virol. 70:3807–3814, 1996). Expression of S-phase regulatory proteins (cyclin A, for example) leads to neuronal apoptosis. Consequently, we hypothesize that interactions between LRP and cell cycle regulatory proteins promote survival of postmitotic neurons during acute infection and/or reactivation.

scholarly journals Multiple Functions of Fubp1 in Cell Cycle Progression and Cell Survival

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1347 ◽  
Author(s):  
Mingyu Kang ◽  
Hyeon Ji Kim ◽  
Tae-Jun Kim ◽  
Jin-Seok Byun ◽  
Jae-Ho Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Metabolic Stress ◽  
Cyclin A ◽  
S Phase ◽  
Cycle Progression ◽  
Genes Encoding ◽  
Double Agent

The discovery of novel and critical genes implicated in malignant development is a topic of high interest in cancer research. Intriguingly, a group of genes named “double-agent” genes were reported to have both oncogenic and tumor-suppressive functions. To date, less than 100 “double-agent” genes have been documented. Fubp1 is a master transcriptional regulator of a subset of genes by interacting with a far upstream element (FUSE). Mounting evidence has collectively demonstrated both the oncogenic and tumor suppressive roles of Fubp1 and the debate regarding its roles in tumorigenesis has been around for several years. Therefore, the detailed molecular mechanisms of Fubp1 need to be determined in each context. In the present study, we showed that the Fubp1 protein level was enriched in the S phase and we identified that Fubp1 deficiency altered cell cycle progression, especially in the S phase, by downregulating the mRNA expression levels of Ccna genes encoding cyclin A. Although this Fubp1-cyclin A axis appears to exist in several types of tumors, Fubp1 showed heterogeneous expression patterns among various cancer tissues, suggesting it exhibits multiple and complicated functions in cancer development. In addition, we showed that Fubp1 deficiency confers survival advantages to cells against metabolic stress and anti-cancer drugs, suggesting that Fubp1 may play both positive and negative roles in malignant development.

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