scholarly journals ChIP-exo analysis highlights Fkh1 and Fkh2 transcription factors as hubs that integrate multi-scale networks in budding yeast

2019 ◽  
Vol 47 (15) ◽  
pp. 7825-7841 ◽  
Author(s):  
Thierry D G A Mondeel ◽  
Petter Holland ◽  
Jens Nielsen ◽  
Matteo Barberis
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Transcription Factors ◽  
Target Genes ◽  
Budding Yeast ◽  
Biochemical Networks ◽  
Molecular Networks ◽  
Forkhead Transcription Factors ◽  
Multi Scale ◽  
Cellular Environment

AbstractThe understanding of the multi-scale nature of molecular networks represents a major challenge. For example, regulation of a timely cell cycle must be coordinated with growth, during which changes in metabolism occur, and integrate information from the extracellular environment, e.g. signal transduction. Forkhead transcription factors are evolutionarily conserved among eukaryotes, and coordinate a timely cell cycle progression in budding yeast. Specifically, Fkh1 and Fkh2 are expressed during a lengthy window of the cell cycle, thus are potentially able to function as hubs in the multi-scale cellular environment that interlocks various biochemical networks. Here we report on a novel ChIP-exo dataset for Fkh1 and Fkh2 in both logarithmic and stationary phases, which is analyzed by novel and existing software tools. Our analysis confirms known Forkhead targets from available ChIP-chip studies and highlights novel ones involved in the cell cycle, metabolism and signal transduction. Target genes are analyzed with respect to their function, temporal expression during the cell cycle, correlation with Fkh1 and Fkh2 as well as signaling and metabolic pathways they occur in. Furthermore, differences in targets between Fkh1 and Fkh2 are presented. Our work highlights Forkhead transcription factors as hubs that integrate multi-scale networks to achieve proper timing of cell division in budding yeast.

scholarly journals Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Matteo Barberis
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Division ◽  
Design Principle ◽  
Budding Yeast ◽  
Eukaryotic Cell ◽  
Quantitative Model ◽  
Sequential Order ◽  
Forkhead Transcription Factors

AbstractIn budding yeast, synchronization of waves of mitotic cyclins that activate the Cdk1 kinase occur through Forkhead transcription factors. These molecules act as controllers of their sequential order and may account for the separation in time of incompatible processes. Here, a Forkhead-mediated design principle underlying the quantitative model of Cdk control is proposed for budding yeast. This design rationalizes timing of cell division, through progressive and coordinated cyclin/Cdk-mediated phosphorylation of Forkhead, and autonomous cyclin/Cdk oscillations. A “clock unit” incorporating this design that regulates timing of cell division is proposed for both yeast and mammals, and has a DRIVER operating the incompatible processes that is instructed by multiple CLOCKS. TIMERS determine whether the clocks are active, whereas CONTROLLERS determine how quickly the clocks shall function depending on external MODULATORS. This “clock unit” may coordinate temporal waves of cyclin/Cdk concentration/activity in the eukaryotic cell cycle making the driver operate the incompatible processes, at separate times.

scholarly journals Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Matteo Barberis
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Current Knowledge ◽  
Budding Yeast ◽  
Cell Cycle Control ◽  
Eukaryotic Cell ◽  
Quantitative Model ◽  
Forkhead Transcription Factors ◽  
Dynamic Coordination ◽  
Cell Cycle Dynamics

AbstractNetworks of interacting molecules organize topology, amount, and timing of biological functions. Systems biology concepts required to pin down ‘network motifs’ or ‘design principles’ for time-dependent processes have been developed for the cell division cycle, through integration of predictive computer modeling with quantitative experimentation. A dynamic coordination of sequential waves of cyclin-dependent kinases (cyclin/Cdk) with the transcription factors network offers insights to investigate how incompatible processes are kept separate in time during the eukaryotic cell cycle. Here this coordination is discussed for the Forkhead transcription factors in light of missing gaps in the current knowledge of cell cycle control in budding yeast. An emergent design principle is proposed where cyclin waves are synchronized by a cyclin/Cdk-mediated feed-forward regulation through the Forkhead as a transcriptional timer. This design is rationalized by the bidirectional interaction between mitotic cyclins and the Forkhead transcriptional timer, resulting in an autonomous oscillator that may be instrumental for a well-timed progression throughout the cell cycle. The regulation centered around the cyclin/Cdk–Forkhead axis can be pivotal to timely coordinate cell cycle dynamics, thereby to actuate the quantitative model of Cdk control.

Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors

2003 ◽  
Vol 31 (1) ◽  
pp. 292-297 ◽  
Author(s):  
K.U. Birkenkamp ◽  
P.J. Coffer
Keyword(s):  
Transcription Factors ◽  
Cell Survival ◽  
Cell Fate ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Acute Lymphocytic Leukaemia ◽  
Cell Fate Decisions ◽  
Forkhead Transcription Factors ◽  
Forkhead Box

Recently, the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors has been identified as direct targets of phosphoinositide 3-kinase-mediated signal transduction. The AFX (acute-lymphocytic-leukaemia-1 fused gene from chromosome X), FKHR (Forkhead in rhabdomyosarcoma) and FKHR-L1 (FKHR-like 1) transcription factors are directly phosphorylated by protein kinase B, resulting in nuclear export and inhibition of transcription. This signalling pathway was first identified in the nematode worm Caenorhabditis elegans, where it has a role in regulation of the life span of the organism. Studies have shown that this evolutionarily conserved signalling module has a role in regulation of both cell-cycle progression and cell survival in higher eukaryotes. These effects are co-ordinated by FOXO-mediated induction of a variety of specific target genes that are only now beginning to be identified. Interestingly, FOXO transcription factors appear to be able to regulate transcription through both DNA-binding-dependent and -independent mechanisms. Our understanding of the regulation of FOXO activity, and defining specific transcriptional targets, may provide clues to the molecular mechanisms controlling cell fate decisions to divide, differentiate or die.

Grainyhead-like Transcription Factors in Craniofacial Development

2017 ◽  
Vol 96 (11) ◽  
pp. 1200-1209 ◽  
Author(s):  
M.R. Carpinelli ◽  
M.E. de Vries ◽  
S.M. Jane ◽  
S. Dworkin
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Current Knowledge ◽  
Craniofacial Development ◽  
Molecular Networks ◽  
Multiple Model ◽  
Therapeutic Measures ◽  
Formation Conditions ◽  
Maxilla And Mandible ◽  
Craniofacial Defects

Craniofacial development in vertebrates involves the coordinated growth, migration, and fusion of several facial prominences during embryogenesis, processes governed by strict genetic and molecular controls. A failure in any of the precise spatiotemporal sequences of events leading to prominence fusion often leads to anomalous facial, skull, and jaw formation—conditions termed craniofacial defects (CFDs). Affecting approximately 0.1% to 0.3% of live births, CFDs are a highly heterogeneous class of developmental anomalies, which are often underpinned by genetic mutations. Therefore, identifying novel disease-causing mutations in genes that regulate craniofacial development is a critical prerequisite to develop new preventive or therapeutic measures. The Grainyhead-like ( GRHL) transcription factors are one such gene family, performing evolutionarily conserved roles in craniofacial patterning. The antecedent member of this family, Drosophila grainyhead ( grh), is required for head skeleton development in fruit flies, loss or mutation of Grhl family members in mouse and zebrafish models leads to defects of both maxilla and mandible, and recently, mutations in human GRHL3 have been shown to cause or contribute to both syndromic (Van Der Woude syndrome) and nonsyndromic palatal clefts. In this review, we summarize the current knowledge regarding the craniofacial-specific function of the Grainyhead-like family in multiple model species, identify some of the major target genes regulated by the Grhl transcription factors in craniofacial patterning, and, by examining animal models, draw inferences as to how these data will inform the likely roles of GRHL factors in human CFDs comprising palatal clefting. By understanding the molecular networks regulated by Grhl2 and Grhl3 target genes in other systems, we can propose likely pathways that mediate the effects of these transcription factors in human palatogenesis.

scholarly journals Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D

2002 ◽  
Vol 22 (22) ◽  
pp. 7842-7852 ◽  
Author(s):  
Marc Schmidt ◽  
Sylvia Fernandez de Mattos ◽  
Armando van der Horst ◽  
Rob Klompmaker ◽  
Geert J. P. L Kops ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Protein Expression ◽  
Cell Cycle Arrest ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Forkhead Transcription Factors ◽  
Cycle Arrest ◽  
Cell Cycle Inhibition

ABSTRACT The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FoxO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27kip1 (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27kip1-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27kip1 function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.

scholarly journals Control of Cyclin G2 mRNA Expression by Forkhead Transcription Factors: Novel Mechanism for Cell Cycle Control by Phosphoinositide 3-Kinase and Forkhead

2004 ◽  
Vol 24 (5) ◽  
pp. 2181-2189 ◽  
Author(s):  
Lorena Martínez-Gac ◽  
Miriam Marqués ◽  
Zaira García ◽  
Miguel R. Campanero ◽  
Ana C. Carrera
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Mrna Expression ◽  
Mrna Levels ◽  
Expression Levels ◽  
Forkhead Transcription Factors ◽  
Cell Cycle Entry ◽  
Cyclin G2 ◽  
Phosphoinositide 3 Kinase ◽  
Mrna Expression Levels

ABSTRACT Cyclin G2 is an unconventional cyclin highly expressed in postmitotic cells. Unlike classical cyclins that promote cell cycle progression, cyclin G2 blocks cell cycle entry. Here we studied the mechanisms that regulate cyclin G2 mRNA expression during the cell cycle. Analysis of synchronized NIH 3T3 cell cultures showed elevated cyclin G2 mRNA expression levels at G0, with a considerable reduction as cells enter cell cycle. Downregulation of cyclin G2 mRNA levels requires activation of phosphoinositide 3-kinase, suggesting that this enzyme controls cyclin G2 mRNA expression. Because the phosphoinositide 3-kinase pathway inhibits the FoxO family of forkhead transcription factors, we examined the involvement of these factors in the regulation of cyclin G2 expression. We show that active forms of the forkhead transcription factor FoxO3a (FKHRL1) increase cyclin G2 mRNA levels. Cyclin G2 has forkhead consensus motifs in its promoter, which are transactivated by constitutive active FoxO3a forms. Finally, interference with forkhead-mediated transcription by overexpression of an inactive form decreases cyclin G2 mRNA expression levels. These results show that FoxO genes regulate cyclin G2 expression, illustrating a new role for phosphoinositide 3-kinase and FoxO transcription factors in the control of cell cycle entry.

scholarly journals Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits

2020 ◽  
Author(s):  
Corvin D. Arveseth ◽  
John T. Happ ◽  
Danielle S. Hedeen ◽  
Ju-Fen Zhu ◽  
Jacob L. Capener ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Transcription Factors ◽  
Target Genes ◽  
Catalytic Subunits ◽  
Unknown Mechanism ◽  
Gli Transcription Factors ◽  
Intracellular Domains ◽  
G Protein Coupled ◽  
Activity Dependent ◽  
Kinase A

ABSTRACTThe Hedgehog (Hh) pathway is essential for organ development, homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase 2 (GRK2)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.

scholarly journals Anthocyanin-Enriched Riceberry Rice Extract Inhibits Cell Proliferation and Adipogenesis in 3T3-L1 Preadipocytes by Downregulating Adipogenic Transcription Factors and Their Targeting Genes

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2480
Author(s):  
Phutthida Kongthitilerd ◽  
Tanyawan Suantawee ◽  
Henrique Cheng ◽  
Thavaree Thilavech ◽  
Marisa Marnpae ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Intracellular Calcium ◽  
Glucose Uptake ◽  
Target Genes ◽  
Oryza Sativa L ◽  
Adipogenic Differentiation ◽  
Anthocyanin Content ◽  
Triglyceride Accumulation

Riceberry rice (Oryza sativa L.) is a new pigmented variety of rice from Thailand. Despite its high anthocyanin content, its effect on adipogenesis and adipocyte function remains unexplored. We investigated whether Riceberry rice extract (RBE) impacted cell proliferation by examining viability and cell cycle, using preadipocyte 3T3-L1 cells. To test RBE’s effect on adipocyte formation, cells were cultured in adipogenic medium supplemented with extract and adipocyte number and triglyceride levels were quantified. Furthermore, Akt1 phosphorylation along with RT-qPCR and intracellular calcium imaging were performed to obtain an insight into its mechanism of action. The effect of RBE on adipocyte function was investigated using glucose uptake and lipolysis assays. Treatment of cells with RBE decreased preadipocyte number without cytotoxicity despite inducing cell cycle arrest (p < 0.05). During adipogenic differentiation, RBE supplementation reduced adipocyte number and triglyceride accumulation by downregulating transcription factors (e.g., PPARγ, C/EBPα, and C/EBPβ) and their target genes (p < 0.05). The Akt1 phosphorylation was decreased by RBE but insignificance, however, the extract failed to increase intracellular calcium signals. Finally, the treatment of adipocytes with RBE reduced glucose uptake by downregulating Glut4 mRNA expression and enhanced isoproterenol-induced lipolysis (p < 0.05). These findings suggest that RBE could potentially be used in the treatment of obesity by inhibiting adipocyte formation and proliferation.

Metabolic enzymes regulated by the Myc oncogene are possible targets for chemotherapy or chemoprevention

2007 ◽  
Vol 35 (2) ◽  
pp. 305-310 ◽  
Author(s):  
S. Rimpi ◽  
J.A. Nilsson
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Recent Work ◽  
Target Genes ◽  
Biological Effects ◽  
Metabolic Enzymes ◽  
Myc Oncogene ◽  
E Box ◽  
Genes Encoding ◽  
Cell Cycle Machinery

The Myc oncogenes are dysregulated in 70% of human cancers. They encode transcription factors that bind to E-box sequences in DNA, driving the expression of a vast amount of target genes. The biological outcome is enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Based on the biological effects of Myc overexpression it was originally assumed that the important Myc target genes are those encoding components of the cell cycle machinery. Recent work has challenged this notion and indicates that Myc target genes encoding metabolic enzymes deserve attention, as they may be critical arbiters of Myc in cancer. Thus targeting metabolic enzymes encoded by Myc-target genes may provide a new means to treat cancer that have arisen in response to deregulated Myc oncogenes.

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