Regulation of Meiosis Initiation before the Commitment Point in Budding Yeast: A Review of Biology, Molecular Mechanisms and Related Mathematical Models

The initial kinetochore (KT) encounter with a spindle microtubule (MT; KT capture) is one of the rate-limiting steps in establishing proper KT–MT interaction during mitosis. KT capture is facilitated by multiple factors, such as MT extension in various directions, KT diffusion, and MT pivoting. In addition, KTs generate short MTs, which subsequently interact with a spindle MT. KT-derived MTs may facilitate KT capture, but their contribution is elusive. In this study, we find that Stu1 recruits Stu2 to budding yeast KTs, which promotes MT generation there. By removing Stu2 specifically from KTs, we show that KT-derived MTs shorten the half-life of noncaptured KTs from 48–49 s to 28–34 s. Using computational simulation, we found that multiple factors facilitate KT capture redundantly or synergistically. In particular, KT-derived MTs play important roles both by making a significant contribution on their own and by synergistically enhancing the effects of KT diffusion and MT pivoting. Our study reveals fundamental mechanisms facilitating the initial KT encounter with spindle MTs.

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Yeast as a Model to Understand Actin-Mediated Cellular Functions in Mammals—Illustrated with Four Actin Cytoskeleton Proteins

Cells ◽

10.3390/cells9030672 ◽

2020 ◽

Vol 9 (3) ◽

pp. 672 ◽

Cited By ~ 1

Author(s):

Zain Akram ◽

Ishtiaq Ahmed ◽

Heike Mack ◽

Ramandeep Kaur ◽

Richard C. Silva ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Molecular Mechanisms ◽

Budding Yeast ◽

Animal Cell ◽

Molecular Genetic ◽

In Vivo Studies ◽

Yeast Saccharomyces Cerevisiae ◽

Higher Eukaryotes

The budding yeast Saccharomyces cerevisiae has an actin cytoskeleton that comprises a set of protein components analogous to those found in the actin cytoskeletons of higher eukaryotes. Furthermore, the actin cytoskeletons of S. cerevisiae and of higher eukaryotes have some similar physiological roles. The genetic tractability of budding yeast and the availability of a stable haploid cell type facilitates the application of molecular genetic approaches to assign functions to the various actin cytoskeleton components. This has provided information that is in general complementary to that provided by studies of the equivalent proteins of higher eukaryotes and hence has enabled a more complete view of the role of these proteins. Several human functional homologues of yeast actin effectors are implicated in diseases. A better understanding of the molecular mechanisms underpinning the functions of these proteins is critical to develop improved therapeutic strategies. In this article we chose as examples four evolutionarily conserved proteins that associate with the actin cytoskeleton: (1) yeast Hof1p/mammalian PSTPIP1, (2) yeast Rvs167p/mammalian BIN1, (3) yeast eEF1A/eEF1A1 and eEF1A2 and (4) yeast Yih1p/mammalian IMPACT. We compare the knowledge on the functions of these actin cytoskeleton-associated proteins that has arisen from studies of their homologues in yeast with information that has been obtained from in vivo studies using live animals or in vitro studies using cultured animal cell lines.

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Epithelial-mesenchymal plasticity: How have quantitative mathematical models helped improve our understanding?

10.1101/122036 ◽

2017 ◽

Author(s):

Mohit Kumar Jolly ◽

Satyendra C Tripathi ◽

Jason A Somarelli ◽

Samir M Hanash ◽

Herbert Levine

Keyword(s):

Phenotypic Plasticity ◽

Mathematical Models ◽

Tumor Progression ◽

Immune Evasion ◽

Molecular Mechanisms ◽

Invasion And Metastasis ◽

Hallmarks Of Cancer ◽

Mesenchymal Phenotype ◽

Extracellular Signals ◽

Clinical Challenge

AbstractPhenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well-studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune-evasion, and invasion and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally-verified molecular mechanisms and act as ‘ hypothesis-generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive epithelial-mesenchymal plasticity at both the single-cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression.

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Genomic Instability and Cellular Senescence: Lessons From the Budding Yeast

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.619126 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jee Whu Lee ◽

Eugene Boon Beng Ong

Keyword(s):

Ribosomal Dna ◽

Cellular Senescence ◽

Molecular Mechanisms ◽

Budding Yeast ◽

Genetic Alterations ◽

Lessons Learned ◽

Complex Biological Process ◽

Dna Instability ◽

Permanent Cell ◽

Living Organisms

Aging is a complex biological process that occurs in all living organisms. Aging is initiated by the gradual accumulation of biomolecular damage in cells leading to the loss of cellular function and ultimately death. Cellular senescence is one such pathway that leads to aging. The accumulation of nucleic acid damage and genetic alterations that activate permanent cell-cycle arrest triggers the process of senescence. Cellular senescence can result from telomere erosion and ribosomal DNA instability. In this review, we summarize the molecular mechanisms of telomere length homeostasis and ribosomal DNA stability, and describe how these mechanisms are linked to cellular senescence and longevity through lessons learned from budding yeast.

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Molecular Mechanisms and Targets of Cyclic Guanosine Monophosphate (cGMP) in Vascular Smooth Muscles

10.5772/intechopen.97708 ◽

2021 ◽

Author(s):

Aleš Fajmut

Keyword(s):

Mathematical Models ◽

Molecular Mechanisms ◽

Soluble Guanylate Cyclase ◽

Smooth Muscles ◽

Cytosolic Calcium ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Vascular Smooth Muscles ◽

Ip3 Receptor ◽

Cl Channels

Molecular mechanisms and targets of cyclic guanosine monophosphate (cGMP) accounting for vascular smooth muscles (VSM) contractility are reviewed. Mathematical models of five published mechanisms are presented, and four novel mechanisms are proposed. cGMP, which is primarily produced by the nitric oxide (NO) dependent soluble guanylate cyclase (sGC), activates cGMP-dependent protein kinase (PKG). The NO/cGMP/PKG signaling pathway targets are the mechanisms that regulate cytosolic calcium ([Ca2+]i) signaling and those implicated in the Ca2+-desensitization of the contractile apparatus. In addition to previous mathematical models of cGMP-mediated molecular mechanisms targeting [Ca2+]i regulation, such as large-conductance Ca2+-activated K+ channels (BKCa), Ca2+-dependent Cl− channels (ClCa), Na+/Ca2+ exchanger (NCX), Na+/K+/Cl− cotransport (NKCC), and Na+/K+-ATPase (NKA), other four novel mechanisms are proposed here based on the existing but perhaps overlooked experimental results. These are the effects of cGMP on the sarco−/endo- plasmic reticulum Ca2+-ATPase (SERCA), the plasma membrane Ca2+-ATPase (PMCA), the inositol 1,4,5-trisphosphate (IP3) receptor channels type 1 (IP3R1), and on the myosin light chain phosphatase (MLCP), which is implicated in the Ca2+-desensitization. Different modeling approaches are presented and discussed, and novel model descriptions are proposed.

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The class V myosin motor protein, Myo2, plays a major role in mitochondrial motility in Saccharomyces cerevisiae

The Journal of Cell Biology ◽

10.1083/jcb.200709099 ◽

2008 ◽

Vol 181 (1) ◽

pp. 119-130 ◽

Cited By ~ 72

Author(s):

Katrin Altmann ◽

Martina Frank ◽

Daniel Neumann ◽

Stefan Jakobs ◽

Benedikt Westermann

Keyword(s):

Saccharomyces Cerevisiae ◽

Actin Cytoskeleton ◽

Molecular Mechanisms ◽

Budding Yeast ◽

Motor Protein ◽

Mitochondrial Morphology ◽

Direct Role ◽

Class V ◽

Myosin Motor ◽

Mitochondrial Motility

The actin cytoskeleton is essential for polarized, bud-directed movement of cellular membranes in Saccharomyces cerevisiae and thus ensures accurate inheritance of organelles during cell division. Also, mitochondrial distribution and inheritance depend on the actin cytoskeleton, though the precise molecular mechanisms are unknown. Here, we establish the class V myosin motor protein, Myo2, as an important mediator of mitochondrial motility in budding yeast. We found that mutants with abnormal expression levels of Myo2 or its associated light chain, Mlc1, exhibit aberrant mitochondrial morphology and loss of mitochondrial DNA. Specific mutations in the globular tail of Myo2 lead to aggregation of mitochondria in the mother cell. Isolated mitochondria lacking functional Myo2 are severely impaired in their capacity to bind to actin filaments in vitro. Time-resolved fluorescence microscopy revealed a block of bud-directed anterograde mitochondrial movement in cargo binding–defective myo2 mutant cells. We conclude that Myo2 plays an important and direct role for mitochondrial motility and inheritance in budding yeast.

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A multi-state model of chemoresistance to characterize phenotypic dynamics in breast cancer

10.1101/207605 ◽

2017 ◽

Author(s):

Grant R. Howard ◽

Kaitlyn E. Johnson ◽

Areli Rodriguez Ayala ◽

Thomas E. Yankeelov ◽

Amy Brock

Keyword(s):

Breast Cancer ◽

Mathematical Models ◽

Drug Sensitivity ◽

Molecular Mechanisms ◽

Drug Exposure ◽

Population Heterogeneity ◽

State Model ◽

Time Resolved ◽

Sensitivity Data ◽

Mcf 7

AbstractThe development of resistance to chemotherapy is a major cause of treatment failure in breast cancer. Although several molecular mechanisms of chemotherapeutic resistance are well studied, a quantitative understanding of the dynamics of resistant subpopulations within a heterogeneous tumor cell population remains elusive. While mathematical models describing the dynamics of heterogeneous cancer cell populations have been proposed, few have been experimentally validated due to the complex nature of resistance that limits the ability of a single phenotypic marker to sufficiently isolate drug resistant subpopulations. In this work, we address this problem with a combined experimental and modeling system that uses drug sensitivity data to reveal the composition of multiple subpopulations differing in their level of drug resistance. We calibrate time-resolved dose-response data to three mathematical models to interrogate the models’ ability to capture the dynamics of drug. All three models demonstrated an increase in population level resistance following drug exposure. The candidate models were compared by Akaike information criterion and the model selection criteria identified a multi-state model incorporating the role of population heterogeneity and cellular plasticity. To validate the ability of this model to identify the composition of subpopulations, we mixed wild-type MCF-7 and MCF-7/ADR resistant cells at various proportions and evaluated the corresponding model output. Our blinded two-state model was able to estimate the proportions of cell subtypes, with the measured proportions falling within the 95 percent confidence intervals on the parameter estimations and at an R-squared value of 0.986. To the best of our knowledge, this contribution represents the first work to combine experimental time-resolved drug sensitivity data with a mathematical model of resistance development.

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Fifty years of cycling

Molecular Biology of the Cell ◽

10.1091/mbc.e20-07-0495 ◽

2020 ◽

Vol 31 (26) ◽

pp. 2868-2870

Author(s):

Sue Biggins ◽

Lee Hartwell ◽

David Toczyski

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Molecular Mechanisms ◽

Budding Yeast ◽

Current Understanding ◽

Structural Components ◽

Regulatory Enzymes ◽

Molecular Events ◽

Yeast Mutants ◽

Looking Back

Fifty years ago, the first isolation of conditional budding yeast mutants that were defective in cell division was reported. Looking back, we now know that the analysis of these mutants revealed the molecular mechanisms and logic of the cell cycle, identified key regulatory enzymes that drive the cell cycle, elucidated structural components that underly essential cell cycle processes, and influenced our thinking about cancer and other diseases. Here, we briefly summarize what was concluded about the coordination of the cell cycle 50 years ago and how that relates to our current understanding of the molecular events that have since been elucidated.

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