Cell cycle and protein complex dynamics in discovering signaling pathways

Signaling pathways are responsible for the regulation of cell processes, such as monitoring the external environment, transmitting information across membranes, and making cell fate decisions. Given the increasing amount of biological data available and the recent discoveries showing that many diseases are related to the disruption of cellular signal transduction cascades, in silico discovery of signaling pathways in cell biology has become an active research topic in past years. However, reconstruction of signaling pathways remains a challenge mainly because of the need for systematic approaches for predicting causal relationships, like edge direction and activation/inhibition among interacting proteins in the signal flow. We propose an approach for predicting signaling pathways that integrates protein interactions, gene expression, phenotypes, and protein complex information. Our method first finds candidate pathways using a directed-edge-based algorithm and then defines a graph model to include causal activation relationships among proteins, in candidate pathways using cell cycle gene expression and phenotypes to infer consistent pathways in yeast. Then, we incorporate protein complex coverage information for deciding on the final predicted signaling pathways. We show that our approach improves the predictive results of the state of the art using different ranking metrics.

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Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways

Biomolecules ◽

10.3390/biom11101444 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1444

Author(s):

Robert H. Whitaker ◽

Jeanette Gowen Cook

Keyword(s):

Cell Cycle ◽

Cell Survival ◽

Signaling Pathways ◽

Protein Kinases ◽

Cell Fate ◽

P38 Mapk ◽

Cell Function ◽

Cellular Division ◽

Cell Fate Decisions ◽

Bcl2 Family

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways.

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Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates

Journal of Experimental Medicine ◽

10.1084/jem.20050967 ◽

2005 ◽

Vol 202 (11) ◽

pp. 1599-1611 ◽

Cited By ~ 419

Author(s):

Emmanuelle Passegué ◽

Amy J. Wagers ◽

Sylvie Giuriato ◽

Wade C. Anderson ◽

Irving L. Weissman

Keyword(s):

Cell Cycle ◽

Cell Fate ◽

Progenitor Cell ◽

Global Analysis ◽

Molecular Networks ◽

Proliferation Index ◽

Cell Cycle Gene ◽

Hematopoietic Stem ◽

Cell Fate Decisions

Knowledge of the molecular networks controlling the proliferation and fate of hematopoietic stem cells (HSC) is essential to understand their function in maintaining blood cell production during normal hematopoiesis and upon clinical transplantation. Using highly purified stem and progenitor cell populations, we define the proliferation index and status of the cell cycle machinery at discrete stages of hematopoietic differentiation and during cytokine-mediated HSC mobilization. We identify distinct sets of cell cycle proteins that specifically associate with differentiation, self-renewal, and maintenance of quiescence in HSC and progenitor cells. Moreover, we describe a striking inequality of function among in vivo cycling and quiescent HSC by demonstrating that their long-term engraftment potential resides predominantly in the G0 fraction. These data provide a direct link between HSC proliferation and function and identify discrete molecular targets in regulating HSC cell fate decisions that could have implications for both the therapeutic use of HSC and the understanding of leukemic transformation.

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PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1

Oncogenesis ◽

10.1038/s41389-021-00332-z ◽

2021 ◽

Vol 10 (5) ◽

Author(s):

Lucas Schneider ◽

Stefanie Herkt ◽

Lei Wang ◽

Christine Feld ◽

Josephine Wesely ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Transcription Factors ◽

Cyclin D1 ◽

Cell Fate ◽

Target Genes ◽

Specific Gene ◽

Cell Fate Decisions ◽

Rational Development ◽

Differentiation And Proliferation

AbstractThe establishment of cell type specific gene expression by transcription factors and their epigenetic cofactors is central for cell fate decisions. Protein arginine methyltransferase 6 (PRMT6) is an epigenetic regulator of gene expression mainly through methylating arginines at histone H3. This way it influences cellular differentiation and proliferation. PRMT6 lacks DNA-binding capability but is recruited by transcription factors to regulate gene expression. However, currently only a limited number of transcription factors have been identified, which facilitate recruitment of PRMT6 to key cell cycle related target genes. Here, we show that LEF1 contributes to the recruitment of PRMT6 to the central cell cycle regulator CCND1 (Cyclin D1). We identified LEF1 as an interaction partner of PRMT6. Knockdown of LEF1 or PRMT6 reduces CCND1 expression. This is in line with our observation that knockdown of PRMT6 increases the number of cells in G1 phase of the cell cycle and decreases proliferation. These results improve the understanding of PRMT6 activity in cell cycle regulation. We expect that these insights will foster the rational development and usage of specific PRMT6 inhibitors for cancer therapy.

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First person – Nadine Pollak

Journal of Cell Science ◽

10.1242/jcs.259602 ◽

2021 ◽

Vol 134 (24) ◽

Keyword(s):

Cell Cycle ◽

Cell Fate ◽

Cell Biology ◽

Cell Cycle Progression ◽

Early Career ◽

First Person ◽

Apoptosis Resistance ◽

Cycle Progression ◽

Cell Fate Decisions ◽

Extrinsic Apoptosis

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Nadine Pollak is first author on ‘ Cell cycle progression and transmitotic apoptosis resistance promote escape from extrinsic apoptosis’, published in JCS. Nadine conducted the research described in this article while a postdoc at the Institute of Cell Biology and Immunology, University of Stuttgart, Germany, initially under the supervision of Prof. Peter Scheurich and subsequently in the lab of Prof. Markus Rehm, where she is now investigating the mechanisms underlying cell fate decisions in response to death stimuli throughout the cell cycle at the single-cell level.

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Ethanol alters cell cycle gene expression in human embryonic stem cells

Journal of Pediatric Biochemistry ◽

10.1055/s-0036-1586381 ◽

2016 ◽

Vol 01 (03) ◽

pp. 201-208 ◽

Cited By ~ 2

Author(s):

Malini Krishnamoorthy ◽

Brian Gerwe ◽

Jamie Heimburg-Molinaro ◽

Rachel Nash ◽

Jagan Arumugham ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Cell Cycle Gene ◽

Cell Cycle Gene Expression

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Low phosphate signaling induces changes in cell cycle gene expression by increasing auxin sensitivity in the Arabidopsis root system

Plant Signaling & Behavior ◽

10.4161/psb.4.8.9230 ◽

2009 ◽

Vol 4 (8) ◽

pp. 781-783 ◽

Cited By ~ 13

Author(s):

Claudia-Anahí Pérez-Torres ◽

José López-Bucio ◽

Luis Herrera Estrella

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Root System ◽

Cell Cycle Gene ◽

Arabidopsis Root ◽

Cell Cycle Gene Expression

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GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02259-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mika J. Välimäki ◽

Robert S. Leigh ◽

Sini M. Kinnunen ◽

Alexander R. March ◽

Ana Hernández de Sande ◽

...

Keyword(s):

Gene Expression ◽

Progenitor Cells ◽

Cell Fate ◽

Reporter Gene ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Cell Fate Decisions ◽

Dual Reporter ◽

Gene Regulatory ◽

Reporter Gene Assays

AbstractBackgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.MethodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.ResultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.ConclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

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