scholarly journals Multiple inputs ensure yeast cell size homeostasis during cell cycle progression

2017 ◽  
Author(s):  
Cecilia Garmendia-Torres ◽  
Olivier Tassy ◽  
Audrey Matifas ◽  
Nacho Molina ◽  
Gilles Charvin
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Size Control ◽  
Large Cell ◽  
Yeast Cells ◽  
Cycle Progression ◽  
Size Variability

AbstractCoordination of cell growth and division is essential for proper cell function. In budding yeast, although some molecular mechanisms responsible for cell size control during G1 have been elucidated, the mechanism by which cell size homeostasis is established and maintained throughout the cell cycle remains to be discovered. Here, we developed a new technique based on quantification of histone levels to monitor cell cycle progression in individual yeast cells with unprecedented accuracy. Our analysis establishes the existence of a strong mechanism controlling bud size in G2/M that prevents premature entry into mitosis, and contributes significantly to the overall control of size variability during the cell cycle. While most G1/S regulation mutants do not display any strongly impaired size homeostasis, mutants in which B-type cyclin regulation is altered display large cell-to-cell size variability. Our study thus demonstrates that size homeostasis is not controlled by a G1-specific mechanism but is likely to be an emergent property resulting from the integration of several mechanisms, including the control of cyclin B-Cdk activity, that coordinate cell and bud growth with division.

scholarly journals Multiple inputs ensure yeast cell size homeostasis during cell cycle progression

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Cecilia Garmendia-Torres ◽  
Olivier Tassy ◽  
Audrey Matifas ◽  
Nacho Molina ◽  
Gilles Charvin
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Size Control ◽  
Cycle Progression ◽  
Bud Size ◽  
Size Variability ◽  
A New Technique

Coordination of cell growth with division is essential for proper cell function. In budding yeast, although some molecular mechanisms responsible for cell size control during G1 have been elucidated, the mechanism by which cell size homeostasis is established remains to be discovered. Here, we developed a new technique based on quantification of histone levels to monitor cell cycle progression in individual cells with unprecedented accuracy. Our analysis establishes the existence of a mechanism controlling bud size in G2/M that prevents premature onset of anaphase, and controls the overall size variability. While most G1 mutants do not display impaired size homeostasis, mutants in which cyclin B-Cdk regulation is altered display large size variability. Our study thus demonstrates that size homeostasis is not controlled by a G1-specific mechanism alone but is likely to be an emergent property resulting from the integration of several mechanisms that coordinate cell and bud growth with division.

scholarly journals Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

2017 ◽  
Author(s):  
Shixuan Liu ◽  
Miriam B. Ginzberg ◽  
Nish Patel ◽  
Marc Hild ◽  
Bosco Leung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
P38 Mapk ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Small Cells ◽  
Animal Cells ◽  
Cycle Progression ◽  
Size Uniformity

AbstractAnimal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.One-sentence summaryThe p38 MAP kinase pathway coordinates cell growth and cell cycle progression by lengthening G1 in small cells, allowing them more time to grow before their next division.

scholarly journals Growth Rate and Cell Size Modulate the Synthesis of, and Requirement for, G1-Phase Cyclins at Start

2004 ◽  
Vol 24 (24) ◽  
pp. 10802-10813 ◽  
Author(s):  
Brandt L. Schneider ◽  
Jian Zhang ◽  
J. Markwardt ◽  
George Tokiwa ◽  
Tom Volpe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Cell Size ◽  
Cell Cycle Progression ◽  
Control Mechanism ◽  
Size Control ◽  
Small Cells ◽  
Critical Threshold ◽  
Cycle Progression

ABSTRACT In Saccharomyces cerevisiae, commitment to cell cycle progression occurs at Start. Progression past Start requires cell growth and protein synthesis, a minimum cell size, and G1-phase cyclins. We examined the relationships among these factors. Rapidly growing cells expressed, and required, dramatically more Cln protein than did slowly growing cells. To clarify the role of cell size, we expressed defined amounts of CLN mRNA in cells of different sizes. When Cln was expressed at nearly physiological levels, a critical threshold of Cln expression was required for cell cycle progression, and this critical threshold varied with both cell size and growth rate: as cells grew larger, they needed less CLN mRNA, but as cells grew faster, they needed more Cln protein. At least in part, large cells had a reduced requirement for CLN mRNA because large cells generated more Cln protein per unit of mRNA than did small cells. When Cln was overexpressed, it was capable of promoting Start rapidly, regardless of cell size or growth rate. In summary, the amount of Cln required for Start depends dramatically on both cell size and growth rate. Large cells generate more Cln1 or Cln2 protein for a given amount of CLN mRNA, suggesting the existence of a novel posttranscriptional size control mechanism.

scholarly journals A Forkhead Transcription Factor Is Important for True Hyphal as well as Yeast Morphogenesis in Candida albicans

2002 ◽  
Vol 1 (5) ◽  
pp. 787-798 ◽  
Author(s):  
Eric S. Bensen ◽  
Scott G. Filler ◽  
Judith Berman
Keyword(s):  
Cell Cycle ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Hyphal Growth ◽  
Growth Conditions ◽  
Yeast Cells ◽  
Cycle Progression ◽  
Forkhead Transcription Factors

ABSTRACT Candida albicans is an important pathogen of immunocompromised patients which grows with true hyphal, pseudohyphal, and yeast morphologies. The dynamics of cell cycle progression are markedly different in true hyphal relative to pseudohyphal and yeast cells, including nuclear movement and septin ring positioning. In Saccharomyces cerevisiae, two forkhead transcription factors (ScFKH1 and ScFKH2) regulate the expression of B-cyclin genes. In both S. cerevisiae and Schizosaccharomyces pombe, forkhead transcription factors also influence morphogenesis. To explore the molecular mechanisms that connect C. albicans morphogenesis with cell cycle progression, we analyzed CaFKH2, the single homolog of S. cerevisiae FKH1/FKH2. C. albicans cells lacking CaFkh2p formed constitutive pseudohyphae under all yeast and hyphal growth conditions tested. Under hyphal growth conditions levels of hyphae-specific mRNAs were reduced, and under yeast growth conditions levels of several genes encoding proteins likely to be important for cell wall separation were reduced. Together these results imply that Fkh2p is required for the morphogenesis of true hyphal as well as yeast cells. Efg1p and Cph1p, two transcription factors that contribute to C. albicans hyphal growth, were not required for the pseudohyphal morphology of fkh2 mutants, implying that Fkh2p acts in pathways downstream of and/or parallel to Efg1p and Cph1p. In addition, cells lacking Fkh2p were unable to damage human epithelial or endothelial cells in vitro, suggesting that Fkh2p contributes to C. albicans virulence.

scholarly journals Effects of 5′-3′ Exonuclease Xrn1 on Cell Size, Proliferation and Division, and mRNA Levels of Periodic Genes in Cryptococcus neoformans

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 430
Author(s):  
Xueru Zhao ◽  
Xin Li ◽  
Ping Zhang ◽  
Chenxi Li ◽  
Weijia Feng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cryptococcus Neoformans ◽  
Cell Size ◽  
Dna Content ◽  
Cell Cycle Progression ◽  
Polymerase Activity ◽  
Yeast Cells ◽  
Mrna Levels ◽  
Cancer Disease ◽  
Cycle Progression

Cell size affects almost all biosynthetic processes by controlling the size of organelles and disrupting the nutrient uptake process. Yeast cells must reach a critical size to be able to enter a new cell cycle stage. Abnormal changes in cell size are often observed under pathological conditions such as cancer disease. Thus, cell size must be strictly controlled during cell cycle progression. Here, we reported that the highly conserved 5′-3′ exonuclease Xrn1 could regulate the gene expression involved in the cell cycle pathway of Cryptococcus neoformans. Chromosomal deletion of XRN1 caused an increase in cell size, defects in cell growth and altered DNA content at 37 °C. RNA-sequencing results showed that the difference was significantly enriched in genes involved in membrane components, DNA metabolism, integration and recombination, DNA polymerase activity, meiotic cell cycle, nuclear division, organelle fission, microtubule-based process and reproduction. In addition, the proportion of the differentially expressed periodic genes was up to 19.8% when XRN1 was deleted, including cell cycle-related genes, chitin synthase genes and transcription factors, indicating the important role of Xrn1 in the control of cell cycle. This work provides insights into the roles of RNA decay factor Xrn1 in maintaining appropriate cell size, DNA content and cell cycle progression.

scholarly journals LMNB2 promotes the progression of colorectal cancer by silencing p21 expression

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Chen-Hua Dong ◽  
Tao Jiang ◽  
Hang Yin ◽  
Hu Song ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Gene Set Enrichment Analysis ◽  
Molecular Therapy ◽  
Cycle Progression ◽  
Cancer Tissues

AbstractColorectal cancer is the second common cause of death worldwide. Lamin B2 (LMNB2) is involved in chromatin remodeling and the rupture and reorganization of nuclear membrane during mitosis, which is necessary for eukaryotic cell proliferation. However, the role of LMNB2 in colorectal cancer (CRC) is poorly understood. This study explored the biological functions of LMNB2 in the progression of colorectal cancer and explored the possible molecular mechanisms. We found that LMNB2 was significantly upregulated in primary colorectal cancer tissues and cell lines, compared with paired non-cancerous tissues and normal colorectal epithelium. The high expression of LMNB2 in colorectal cancer tissues is significantly related to the clinicopathological characteristics of the patients and the shorter overall and disease-free cumulative survival. Functional analysis, including CCK8 cell proliferation test, EdU proliferation test, colony formation analysis, nude mouse xenograft, cell cycle, and apoptosis analysis showed that LMNB2 significantly promotes cell proliferation by promoting cell cycle progression in vivo and in vitro. In addition, gene set enrichment analysis, luciferase report analysis, and CHIP analysis showed that LMNB2 promotes cell proliferation by regulating the p21 promoter, whereas LMNB2 has no effect on cell apoptosis. In summary, these findings not only indicate that LMNB2 promotes the proliferation of colorectal cancer by regulating p21-mediated cell cycle progression, but also suggest the potential value of LMNB2 as a clinical prognostic marker and molecular therapy target.

Abstract W P198: Sphingomyelin Synthases Regulate Neuronal Cell Proliferation and Cell Cycle Progression

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Umadevi V Wesley ◽  
Daniel Tremmel ◽  
Robert Dempsey
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Cycle Regulation ◽  
Cerebral Artery Occlusion

Introduction: The molecular mechanisms of cerebral ischemia damage and protection are not completely understood, but a number of reports implicate the contribution of lipid metabolism and cell-cycle regulating proteins in stroke out come. We have previously shown that tricyclodecan-9-yl-xanthogenate (D609) resulted in increased ceramide levels after transient middle cerebral artery occlusion (tMCAO) in spontaneously hypertensive rat (SHR). We hypothesized that D609 induced cell cycle arrest probably by inhibiting sphingomyelin synthase (SMS). In this study, we examined the direct effects of SMS on cell cycle progression and proliferation of neuroblast cells. Methods: Ischemia was induced by middle cerebral artery occlusion (MCAO) and reperfusion. Expression levels were measured by western blot analysis, RT-PCR, and Immunofluorescence staining. SMS1 and 2 expressions were silenced by stable transfection with SMS1/2-targeted shRNA. Cell cycle analysis was performed using Flow cytometry. Data were analyzed using MODFIT cell cycle analysis program. Cell proliferation rate was measured by MTT assay. Results: We have identified that the expression of SMS1is significantly up-regulated in the ischemic hemisphere following MCAO. Neuro-2a cells transfected with SMS specific ShRNA acquired more neuronal like phenotype and exhibited decreased proliferation rate. Also, silencing of both SMS1 and 2 induced cell-cycle arrest as shown by significantly increased percentage of cells in G0/G1 and decreased proportion of cells in S-phase as compared to control cells. This was accompanied by up-regulation of cyclin-dependent kinase (Cdk) inhibitors p21 and decreased levels of phophorylated AKT levels. Furthermore, loss of SMS inhibited the migratory potential of Neuro 2a cells. Summary: Up-regulation of SMS under ischemic/reperfusion conditions suggests that this enzyme potentially contributes to cell cycle regulation and may contribute to maintaining neuronal cell population. Further studies may open up a new direction for identifying the molecular mechanisms of cell cycle regulation and protection following ischemic stroke

scholarly journals Molecular Mechanisms Underlying Yatein-Induced Cell-Cycle Arrest and Microtubule Destabilization in Human Lung Adenocarcinoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1384 ◽  
Author(s):  
Shang-Tse Ho ◽  
Chi-Chen Lin ◽  
Yu-Tang Tung ◽  
Jyh-Horng Wu
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Lung Adenocarcinoma ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Microtubule Dynamics ◽  
Cycle Progression ◽  
Human Lung Adenocarcinoma

Yatein is an antitumor agent isolated from Calocedrus formosana Florin leaves extract. In our previous study, we found that yatein inhibited the growth of human lung adenocarcinoma A549 and CL1-5 cells by inducing intrinsic and extrinsic apoptotic pathways. To further uncover the effects and mechanisms of yatein-induced inhibition on A549 and CL1-5 cell growth, we evaluated yatein-mediated antitumor activity in vivo and the regulatory effects of yatein on cell-cycle progression and microtubule dynamics. Flow cytometry and western blotting revealed that yatein induces G2/M arrest in A549 and CL1-5 cells. Yatein also destabilized microtubules and interfered with microtubule dynamics in the two cell lines. Furthermore, we evaluated the antitumor activity of yatein in vivo using a xenograft mouse model and found that yatein treatment altered cyclin B/Cdc2 complex expression and significantly inhibited tumor growth. Taken together, our results suggested that yatein effectively inhibited the growth of A549 and CL1-5 cells possibly by disrupting cell-cycle progression and microtubule dynamics.

scholarly journals Compartmentalized nodes control mitotic entry signaling in fission yeast

2013 ◽  
Vol 24 (12) ◽  
pp. 1872-1881 ◽  
Author(s):  
Lin Deng ◽  
James B. Moseley
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Fission Yeast ◽  
Cell Polarity ◽  
Cell Cycle Progression ◽  
Interaction Network ◽  
Yeast Cells ◽  
Cell Cortex ◽  
Cycle Progression ◽  
Mitotic Entry

Cell cycle progression is coupled to cell growth, but the mechanisms that generate growth-dependent cell cycle progression remain unclear. Fission yeast cells enter into mitosis at a defined size due to the conserved cell cycle kinases Cdr1 and Cdr2, which localize to a set of cortical nodes in the cell middle. Cdr2 is regulated by the cell polarity kinase Pom1, suggesting that interactions between cell polarity proteins and the Cdr1-Cdr2 module might underlie the coordination of cell growth and division. To identify the molecular connections between Cdr1/2 and cell polarity, we performed a comprehensive pairwise yeast two-hybrid screen. From the resulting interaction network, we found that the protein Skb1 interacted with both Cdr1 and the Cdr1 inhibitory target Wee1. Skb1 inhibited mitotic entry through negative regulation of Cdr1 and localized to both the cytoplasm and a novel set of cortical nodes. Skb1 nodes were distinct structures from Cdr1/2 nodes, and artificial targeting of Skb1 to Cdr1/2 nodes delayed entry into mitosis. We propose that the formation of distinct node structures in the cell cortex controls signaling pathways to link cell growth and division.

NPM-ALK Promotes Cell Cycle Progression through Activation of JNK and c-Jun in Anaplastic Large Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2057-2057
Author(s):  
Vasiliki Leventaki ◽  
Elias Drakos ◽  
Megan Lim ◽  
Kojo S. Elenitoba-Johnson ◽  
Francois-Xavier Claret ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Western Blot ◽  
Anaplastic Large Cell Lymphoma ◽  
Blot Analysis ◽  
Cell Cycle Progression ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Cycle Progression ◽  
Large Cell Lymphoma

Abstract Anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) chimeric protein. NPM-ALK mediates its oncogenic effects through phosphorylation of a number of proteins involved in known signal transduction pathways including PLC, PI3K-AKT and JAK-STAT. ALK+ ALCL cells also are known to overexpress c-Jun, a member of the activator protein-1 (AP-1) transcription factor family that controls cell proliferation, differentiation, growth and apoptosis. Phosphorylation of c-Jun at serine 73 and serine 63 residues substantially increases AP-1 transcriptional activity and the levels of c-Jun protein through an autoregulatory positive feedback loop. In this study, we hypothesized that NPM-ALK activates JNK which , in turn, phosphorylates and activates c-Jun, resulting in uncontrolled cell cycle progression in ALCL. 293T and Jurkat (T-acute lymphoblastic leukemia) cells were transfected with a vector expressing NPM-ALK with active kinase domain (pDest40-NPM-ALK) or a construct lacking NPM-ALK kinase activity (pDest40-K210R) or empty vector. Cells were harvested at 48 hours and analyzed for protein expression by Western blot analysis and for AP-1 activity by luciferase reporter assay. Two ALK+ ALCL cell lines Karpas 299 and SU-DHL-1, found to express high levels of serine phosphorylated and total c-Jun in immunoblots, were treated with JNK (SP600125), ERK (U0126), or ALK (WHI-P154) inhibitors or were transiently transfected with siRNAs specific for JNK1 and c-Jun. Cell proliferation was assessed by MTS assay, and cell cycle was analyzed by BrdU assay or propidium iodide staining and flow cytometry. Forced expression of NPM-ALK in 293T and Jurkat cells resulted in increased levels of JNK and c-Jun phosphorylation in immunoblots and a dramatic increase in AP-1 activity. Conversely, pharmacologic inhibition of ALK activity in Karpas 299 and SU-DHL1 resulted in a concentration-dependent decrease of JNK and c-Jun phosphorylation levels. Co-immunoprecipitation studies revealed that NPM-ALK physically binds to JNK1 and its upstream activator MKK7 in ALK+ ALCL cells. Selective inhibition of JNK, but not ERK, in Karpas 299 and SU-DHL1 decreased the level of c-Jun phosphorylation in a dose-dependent manner as shown by Western blot analysis and in vitro kinase assays. Inhibition of JNK by SP600125 or silencing of the JNK1 gene by siRNA also resulted in decreased cell proliferation associated with decreased AP-1 activity, cell cycle arrest mostly at G2 phase, and up-regulation of the cyclin-dependent inhibitor p21, a transcriptional target of c-Jun. Similarly, silencing of c-Jun by specific siRNA led to decreased S-phase fraction of cell cycle, which was associated with up-regulation of p21 and downregulation of cyclin D3. These findings reveal a novel function of NPM-ALK oncoprotein, phosphorylation and activation of JNK, which may contribute to uncontrolled cell cycle progression through activation of c-Jun. Modulation of JNK or c-Jun activity may be a target for therapy in patients with ALCL.

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