Biochemistry, Genetics and Molecular Biology › Cell Biology

Microtubule and mitosis dynamics

Works Count: 73000

Wikipedia

Description

This cluster of papers explores the regulation and function of microtubules in cell division, with a focus on topics such as mitotic checkpoint, molecular motors, aneuploidy, and the role of kinesin proteins and Aurora kinases. It also delves into the implications of chromosomal instability and the potential applications for cancer therapy.

Keywords

Microtubules; Cell Division; Mitotic Checkpoint; Molecular Motors; Aneuploidy; Kinesin Proteins; Aurora Kinases; Chromosomal Instability; Spindle Assembly; Cancer Therapy

Phytohemagglutinin: an initiator of mitosis in cultures of normal human leukocytes.

1960-05-01

Peter C. Nowell̀

Summary Possible factors responsible for the initiation of mitotic activity in “gradient” cultures of leukocytes from normal human blood were investigated. Variations of temperature, pH, oxygen tension, carbon dioxide tension, … Summary Possible factors responsible for the initiation of mitotic activity in “gradient” cultures of leukocytes from normal human blood were investigated. Variations of temperature, pH, oxygen tension, carbon dioxide tension, plasma and cell concentrations, as well as the amount of agitation, over at least as wide a range as might be encountered in vivo , produced only moderate quantitative changes in mitotic activity. The mucoprotein plant extract, phytohemagglutinin (PHA), employed originally as a means of separating the leukocytes from whole blood in preparing the cultures, was found to be a specific initiator of mitotic activity: in its presence, cell division occurred; in its absence, no mitoses appeared. The studies suggest that the mitogenic action of PHA does not involve mitosis per se but rather the stage preceding mitosis—the alteration of circulating monocytes and large lymphocytes to a state wherein they are capable of division. The relationship of this mitogenic action of PHA to mitotic and premitotic processes in the body remains to be investigated.

Genetic instabilities in human cancers

1998-12-01

Christoph Lengauer , Kenneth W. Kinzler , Bert Vogelstein

Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation

1998-10-01

Hongyi Zhou , Jian Kuang , Ling Zhong +5 more

Mitotic kinases as regulators of cell division and its checkpoints

2001-01-01

Erich A. Nigg

Dynamic instability of microtubule growth

1984-11-01

Tim Mitchison , Marc W. Kirschner

Ubiquitin ligases: cell-cycle control and cancer

2006-04-24

Keiichi I. Nakayama , Keiko Nakayama

Microtubules as a target for anticancer drugs

2004-04-01

Mary Ann Jordan , Leslie Wilson

A protein factor essential for microtubule assembly.

1975-05-01

Murray Weingarten , Arthur H. Lockwood , S Y Hwo +1 more

A heat stable protein essentail for microtubule assembly has been isolated. This protein, which we designate tau (tau), is present in association with tubulin purified from porcine brain by repeated … A heat stable protein essentail for microtubule assembly has been isolated. This protein, which we designate tau (tau), is present in association with tubulin purified from porcine brain by repeated cycles of polymerization. Tau is separated from tubulin by ion exchange chromatography on phosphocellulose. In the absence of tau, tubulin exists entirely as a 6S dimer of two polypeptide chains (alpha and beta tubulin) with a molecular weight of 120,000, which will not assemble into microtubules in vitro. Addition of tau completely restores tubule-forming capacity. Under nonpolymerizing conditions, tau converts 6S dimers to 36S rings-structures which have been implicated as intermediates in tubule formation. Hence, tau appears to act on the 6S tubulin dimer, activating it for polymerization. The unique ability of tau to restore the normal features of in vitro microtubule assembly makes it likely that tau is a major regulator of microtubule formation in cells.

View PDF Chat

p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest.

1994-01-01

Kornélia Polyák , Jun‐ya Kato , Michael J. Solomon +4 more

Cell-cell contact and TGF-beta can arrest the cell cycle in G1. Mv1Lu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin … Cell-cell contact and TGF-beta can arrest the cell cycle in G1. Mv1Lu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin E, and its catalytic subunit, Cdk2. These growth inhibitory signals block Cdk2 activation by raising the threshold level of cyclin E necessary to activate Cdk2. In arrested cells the threshold is set higher than physiological cyclin E levels and is determined by an inhibitor that binds to cyclin E-Cdk2 complexes. A 27-kD protein that binds to and prevents the activation of cyclin E-Cdk2 complexes can be purified from arrested cells but not from proliferating cells, using cyclin E-Cdk2 affinity chromatography. p27 is present in proliferating cells, but it is sequestered and unavailable to interact with cyclin E-Cdk2 complexes. Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.

View PDF Chat

Microtubule Formation in vitro in Solutions Containing Low Calcium Concentrations

1972-09-22

Richard C. Weisenberg

Isolated rat brain tubulin can be repolymerized in vitro in solutions containing adenosine triphosphate or guanosine triphosphate, magnesium ions, and a good calcium chelator. The extreme sensitivity of tubulin to … Isolated rat brain tubulin can be repolymerized in vitro in solutions containing adenosine triphosphate or guanosine triphosphate, magnesium ions, and a good calcium chelator. The extreme sensitivity of tubulin to calcium ions explains the failure of previous efforts to obtain polymerization and suggests a possible mechanism for regulation of microtubule polymerization in vivo.

Dissecting Temporal and Spatial Control of Cytokinesis with a Myosin II Inhibitor

2003-03-13

Aaron F. Straight , Amy Cheung , John Limouze +4 more

Completion of cell division during cytokinesis requires temporally and spatially regulated communication from the microtubule cytoskeleton to the actin cytoskeleton and the cell membrane. We identified a specific inhibitor of … Completion of cell division during cytokinesis requires temporally and spatially regulated communication from the microtubule cytoskeleton to the actin cytoskeleton and the cell membrane. We identified a specific inhibitor of nonmuscle myosin II, blebbistatin, that inhibited contraction of the cleavage furrow without disrupting mitosis or contractile ring assembly. Using blebbistatin and other drugs, we showed that exit from the cytokinetic phase of the cell cycle depends on ubiquitin-mediated proteolysis. Continuous signals from microtubules are required to maintain the position of the cleavage furrow, and these signals control the localization of myosin II independently of other furrow components.

Beyond self-assembly: From microtubules to morphogenesis

1986-05-01

Marc W. Kirschner

Cyclin is degraded by the ubiquitin pathway

1991-01-01

Michael Glotzer , Andrew W. Murray , Marc W. Kirschner

Structure of the αβ tubulin dimer by electron crystallography

1998-01-08

Eva Nogales , Sharon G. Wolf , Kenneth H. Downing

TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival

2003-11-01

Ken Inoki , Tianqing Zhu , Kun‐Liang Guan

View PDF Chat

Checkpoints: Controls That Ensure the Order of Cell Cycle Events

1989-11-03

Leland H. Hartwell , Ted Weinert

The events of the cell cycle of most organisms are ordered into dependent pathways in which the initiation of late events is dependent on the completion of early events. In … The events of the cell cycle of most organisms are ordered into dependent pathways in which the initiation of late events is dependent on the completion of early events. In eukaryotes, for example, mitosis is dependent on the completion of DNA synthesis. Some dependencies can be relieved by mutation (mitosis may then occur before completion of DNA synthesis), suggesting that the dependency is due to a control mechanism and not an intrinsic feature of the events themselves. Control mechanisms enforcing dependency in the cell cycle are here called checkpoints. Elimination of checkpoints may result in cell death, infidelity in the distribution of chromosomes or other organelles, or increased susceptibility to environmental perturbations such as DNA damaging agents. It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.

To cycle or not to cycle: a critical decision in cancer

2001-12-01

Marcos Malumbres , Mariano Barbacid

Microtubule Assembly in the Absence of Added Nucleotides

1973-03-01

Michael L. Shelanski , Felicia Gaskin , Charles R. Cantor

Microtubule assembly is enhanced by the addition of 1 M sucrose or 4 M glycerol to the reassembly mixture. Tubulin can be purified from guinea pig brain readily and in … Microtubule assembly is enhanced by the addition of 1 M sucrose or 4 M glycerol to the reassembly mixture. Tubulin can be purified from guinea pig brain readily and in good yield by two cycles of assembly in glycerol-containing solutions. The tubules assembled in glycerol and sucrose are more stable than tubules formed in the absence of these compounds. Assembly occurs in glycerol or sucrose in the absence of ATP or GTP, but is greatly accelarated by their presence.

View PDF Chat

Computer Visualization of Three-Dimensional Image Data Using IMOD

1996-01-01

James R. Kremer , David N. Mastronarde , J. Richard McIntosh

Small Molecule Inhibitor of Mitotic Spindle Bipolarity Identified in a Phenotype-Based Screen

1999-10-29

Thomas U. Mayer , Tarun M. Kapoor , Stephen J. Haggarty +3 more

Small molecules that perturb specific protein functions are valuable tools for dissecting complex processes in mammalian cells. A combination of two phenotype-based screens, one based on a specific posttranslational modification, … Small molecules that perturb specific protein functions are valuable tools for dissecting complex processes in mammalian cells. A combination of two phenotype-based screens, one based on a specific posttranslational modification, the other visualizing microtubules and chromatin, was used to identify compounds that affect mitosis. One compound, here named monastrol, arrested mammalian cells in mitosis with monopolar spindles. In vitro, monastrol specifically inhibited the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. All previously known small molecules that specifically affect the mitotic machinery target tubulin. Monastrol will therefore be a particularly useful tool for studying mitotic mechanisms.

View PDF Chat

Cell Cycle Checkpoints: Preventing an Identity Crisis

1996-12-06

Stephen J. Elledge

Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions and ensure that critical events such as DNA replication and chromosome segregation are completed … Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions and ensure that critical events such as DNA replication and chromosome segregation are completed with high fidelity. In addition, checkpoints respond to damage by arresting the cell cycle to provide time for repair and by inducing transcription of genes that facilitate repair. Checkpoint loss results in genomic instability and has been implicated in the evolution of normal cells into cancer cells. Recent advances have revealed signal transduction pathways that transmit checkpoint signals in response to DNA damage, replication blocks, and spindle damage. Checkpoint pathways have components shared among all eukaryotes, underscoring the conservation of cell cycle regulatory machinery.

How Proteolysis Drives the Cell Cycle

1996-12-06

Randall W. King , Raymond J. Deshaies , Jan‐Michael Peters +1 more

Oscillations in the activity of cyclin-dependent kinases (CDKs) promote progression through the eukaryotic cell cycle. This review examines how proteolysis regulates CDK activity—by degrading CDK activators or inhibitors—and also how … Oscillations in the activity of cyclin-dependent kinases (CDKs) promote progression through the eukaryotic cell cycle. This review examines how proteolysis regulates CDK activity—by degrading CDK activators or inhibitors—and also how proteolysis may directly trigger the transition from metaphase to anaphase. Proteolysis during the cell cycle is mediated by two distinct ubiquitin-conjugation pathways. One pathway, requiring CDC34, initiates DNA replication by degrading a CDK inhibitor. The second pathway, involving a large protein complex called the anaphase-promoting complex or cyclosome, initiates chromosome segregation and exit from mitosis by degrading anaphase inhibitors and mitotic cyclins. Proteolysis therefore drives cell cycle progression not only by regulating CDK activity, but by directly influencing chromosome and spindle dynamics.

The selectivity of protein kinase inhibitors: a further update

2007-11-28

Jenny Bain , Lorna Plater , Matt Elliott +7 more

The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70–80 protein kinases. On the basis of this information, … The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70–80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)–raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.

View PDF Chat

G1 phase progression: Cycling on cue

1994-11-01

Charles J. Sherr

The spindle-assembly checkpoint in space and time

2007-04-11

Andrea Musacchio , Edward D. Salmon

Kinesin superfamily motor proteins and intracellular transport

2009-09-23

Nobutaka Hirokawa , Yasuko Noda , Yosuke Tanaka +1 more

The axonal transport of mitochondria

2012-01-01

William M. Saxton , Peter J. Hollenbeck

Vigorous transport of cytoplasmic components along axons over substantial distances is crucial for the maintenance of neuron structure and function. The transport of mitochondria, which serves to distribute mitochondrial functions … Vigorous transport of cytoplasmic components along axons over substantial distances is crucial for the maintenance of neuron structure and function. The transport of mitochondria, which serves to distribute mitochondrial functions in a dynamic and non-uniform fashion, has attracted special interest in recent years following the discovery of functional connections among microtubules, motor proteins and mitochondria, and their influences on neurodegenerative diseases. Although the motor proteins that drive mitochondrial movement are now well characterized, the mechanisms by which anterograde and retrograde movement are coordinated with one another and with stationary axonal mitochondria are not yet understood. In this Commentary, we review why mitochondria move and how they move, focusing particularly on recent studies of transport regulation, which implicate control of motor activity by specific cell-signaling pathways, regulation of motor access to transport tracks and static microtubule–mitochondrion linkers. A detailed mechanism for modulating anterograde mitochondrial transport has been identified that involves Miro, a mitochondrial Ca2+-binding GTPase, which with associated proteins, can bind and control kinesin-1. Elements of the Miro complex also have important roles in mitochondrial fission–fusion dynamics, highlighting questions about the interdependence of biogenesis, transport, dynamics, maintenance and degradation.

View PDF Chat

Active and Inactive Protein Kinases: Structural Basis for Regulation

1996-04-01

L.N. Johnson , M.E.M. Noble , David J. Owen

View PDF Chat

Kinesin and Dynein Superfamily Proteins and the Mechanism of Organelle Transport

1998-01-23

Nobutaka Hirokawa

Cells transport and sort proteins and lipids, after their synthesis, to various destinations at appropriate velocities in membranous organelles and protein complexes. Intracellular transport is thus fundamental to cellular morphogenesis … Cells transport and sort proteins and lipids, after their synthesis, to various destinations at appropriate velocities in membranous organelles and protein complexes. Intracellular transport is thus fundamental to cellular morphogenesis and functioning. Microtubules serve as a rail on which motor proteins, such as kinesin and dynein superfamily proteins, convey their cargoes. This review focuses on the molecular mechanism of organelle transport in cells and describes kinesin and dynein superfamily proteins.

Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain

2004-03-01

Raimond B. G. Ravelli , Benoı̂t Gigant , Patrick A. Curmi +4 more

Microtubule nucleation by γ-tubulin complexes

2011-10-12

Justin M. Kollman , Andreas Merdes , Lionel Mourey +1 more

Tumor heterogeneity: Causes and consequences

2009-11-19

Andriy Marusyk , Kornélia Polyák

View PDF Chat

A quantitative atlas of mitotic phosphorylation

2008-08-01

Noah Dephoure , Chunshui Zhou , Judit Villén +4 more

The eukaryotic cell division cycle is characterized by a sequence of orderly and highly regulated events resulting in the duplication and separation of all cellular material into two newly formed … The eukaryotic cell division cycle is characterized by a sequence of orderly and highly regulated events resulting in the duplication and separation of all cellular material into two newly formed daughter cells. Protein phosphorylation by cyclin-dependent kinases (CDKs) drives this cycle. To gain further insight into how phosphorylation regulates the cell cycle, we sought to identify proteins whose phosphorylation is cell cycle regulated. Using stable isotope labeling along with a two-step strategy for phosphopeptide enrichment and high mass accuracy mass spectrometry, we examined protein phosphorylation in a human cell line arrested in the G(1) and mitotic phases of the cell cycle. We report the identification of >14,000 different phosphorylation events, more than half of which, to our knowledge, have not been described in the literature, along with relative quantitative data for the majority of these sites. We observed >1,000 proteins with increased phosphorylation in mitosis including many known cell cycle regulators. The majority of sites on regulated phosphopeptides lie in [S/T]P motifs, the minimum required sequence for CDKs, suggesting that many of the proteins may be CDK substrates. Analysis of non-proline site-containing phosphopeptides identified two unique motifs that suggest there are at least two undiscovered mitotic kinases.

View PDF Chat

Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores

2003-04-28

Claire Ditchfield , Victoria Johnson , Anthony Tighe +6 more

The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, … The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.

View PDF Chat

The rat brain postsynaptic density fraction contains a homolog of the drosophila discs-large tumor suppressor protein

1992-11-01

Kyung-Ok Cho , Carol A. Hunt , Mary B. Kennedy

Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility

1985-08-01

R D Vale , Thomas S. Reese , Michael P. Sheetz

View PDF Chat

Randomization of Left–Right Asymmetry due to Loss of Nodal Cilia Generating Leftward Flow of Extraembryonic Fluid in Mice Lacking KIF3B Motor Protein

1998-12-01

Shigenori Nonaka , Yosuke Tanaka , Yasushi Okada +5 more

View PDF Chat

Cyclin-dependent kinases

2014-06-30

Marcos Malumbres

Cyclin-dependent kinases (CDKs) are protein kinases characterized by needing a separate subunit - a cyclin - that provides domains essential for enzymatic activity. CDKs play important roles in the control … Cyclin-dependent kinases (CDKs) are protein kinases characterized by needing a separate subunit - a cyclin - that provides domains essential for enzymatic activity. CDKs play important roles in the control of cell division and modulate transcription in response to several extra- and intracellular cues. The evolutionary expansion of the CDK family in mammals led to the division of CDKs into three cell-cycle-related subfamilies (Cdk1, Cdk4 and Cdk5) and five transcriptional subfamilies (Cdk7, Cdk8, Cdk9, Cdk11 and Cdk20). Unlike the prototypical Cdc28 kinase of budding yeast, most of these CDKs bind one or a few cyclins, consistent with functional specialization during evolution. This review summarizes how, although CDKs are traditionally separated into cell-cycle or transcriptional CDKs, these activities are frequently combined in many family members. Not surprisingly, deregulation of this family of proteins is a hallmark of several diseases, including cancer, and drug-targeted inhibition of specific members has generated very encouraging results in clinical trials.

View PDF Chat

Cohesins: Chromosomal Proteins that Prevent Premature Separation of Sister Chromatids

1997-10-01

Christine Michaelis , Rafal Ciosk , Kim Nasmyth

View PDF Chat

Microtubule-binding agents: a dynamic field of cancer therapeutics

2010-10-01

Charles Dumontet , Mary Ann Jordan

DNA breaks and chromosome pulverization from errors in mitosis

2012-01-18

Karen Crasta , Neil J. Ganem , Regina Dagher +7 more

View PDF Chat

The Molecular Motor Toolbox for Intracellular Transport

2003-02-01

Ronald D. Vale

View PDF Chat

Mutations of mitotic checkpoint genes in human cancers

1998-03-01

Daniel P. Cahill , Christoph Lengauer , Jian Yu +5 more

A mechanism linking extra centrosomes to chromosomal instability

2009-06-07

Neil J. Ganem , Susana A. Godinho , David Pellman

Flexural rigidity of microtubules and actin filaments measured from thermal fluctuations in shape.

1993-02-15

F. Gittes , B Mickey , Jennifer A. Nettleton +1 more

Microtubules are long, proteinaceous filaments that perform structural functions in eukaryotic cells by defining cellular shape and serving as tracks for intracellular motor proteins. We report the first accurate measurements … Microtubules are long, proteinaceous filaments that perform structural functions in eukaryotic cells by defining cellular shape and serving as tracks for intracellular motor proteins. We report the first accurate measurements of the flexural rigidity of microtubules. By analyzing the thermally driven fluctuations in their shape, we estimated the mean flexural rigidity of taxol-stabilized microtubules to be 2.2 x 10(-23) Nm2 (with 6.4% uncertainty) for seven unlabeled microtubules and 2.1 x 10(-23) Nm2 (with 4.7% uncertainty) for eight rhodamine-labeled microtubules. These values are similar to earlier, less precise estimates of microtubule bending stiffness obtained by modeling flagellar motion. A similar analysis on seven rhodamine-phalloidin-labeled actin filaments gave a flexural rigidity of 7.3 x 10(-26) Nm2 (with 6% uncertainty), consistent with previously reported results. The flexural rigidity of these microtubules corresponds to a persistence length of 5,200 microns showing that a microtubule is rigid over cellular dimensions. By contrast, the persistence length of an actin filament is only approximately 17.7 microns, perhaps explaining why actin filaments within cells are usually cross-linked into bundles. The greater flexural rigidity of a microtubule compared to an actin filament mainly derives from the former's larger cross-section. If tubulin were homogeneous and isotropic, then the microtubule's Young's modulus would be approximately 1.2 GPa, similar to Plexiglas and rigid plastics. Microtubules are expected to be almost inextensible: the compliance of cells is due primarily to filament bending or sliding between filaments rather than the stretching of the filaments themselves.

View PDF Chat

MICROTUBULE POLYMERIZATION DYNAMICS

1997-11-01

Arshad Desai , Timothy J. Mitchison

▪ Abstract The polymerization dynamics of microtubules are central to their biological functions. Polymerization dynamics allow microtubules to adopt spatial arrangements that can change rapidly in response to cellular needs … ▪ Abstract The polymerization dynamics of microtubules are central to their biological functions. Polymerization dynamics allow microtubules to adopt spatial arrangements that can change rapidly in response to cellular needs and, in some cases, to perform mechanical work. Microtubules utilize the energy of GTP hydrolysis to fuel a unique polymerization mechanism termed dynamic instability. In this review, we first describe progress toward understanding the mechanism of dynamic instability of pure tubulin and then discuss the function and regulation of microtubule dynamic instability in living cells.

Cell death by mitotic catastrophe: a molecular definition

2004-04-12

Maria Castedo , Jean‐Luc Perfettini , Thomas Roumier +3 more

CYCLIN-DEPENDENT KINASES: Engines, Clocks, and Microprocessors

1997-11-01

David O. Morgan

▪ Abstract Cyclin-dependent kinases (Cdks) play a well-established role in the regulation of the eukaryotic cell division cycle and have also been implicated in the control of gene transcription and … ▪ Abstract Cyclin-dependent kinases (Cdks) play a well-established role in the regulation of the eukaryotic cell division cycle and have also been implicated in the control of gene transcription and other processes. Cdk activity is governed by a complex network of regulatory subunits and phosphorylation events whose precise effects on Cdk conformation have been revealed by recent crystallographic studies. In the cell, these regulatory mechanisms generate an interlinked series of Cdk oscillators that trigger the events of cell division.

The theory of rotating fluids

1969-09-01

John P. Dugan

Cell cycle proteins as promising targets in cancer therapy

2017-01-27

Tobias Otto , Piotr Siciński

View PDF Chat

Spatiotemporal orchestration of mitosis by cyclin-dependent kinase

2025-06-25

Nitin Kapadia , Paul Nurse | Nature

Abstract Mitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in … Abstract Mitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in the cytoplasm, at the centrosome, initiating mitosis 1–3 . Bistability in CDK activation ensures that the transition is irreversible, but how this unfolds in a spatially compartmentalized cell is unknown 4–8 . Here, using fission yeast, we show that CDK is first activated in the nucleus, and that the bistable responses differ markedly between the nucleus and the cytoplasm, with a stronger response in the nucleus driving mitotic signal propagation from there to the cytoplasm. Abolishing cyclin–CDK localization to the centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting that centrosomal cyclin–CDK acts as a ‘signal relayer’. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, which enables incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and to integrate ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosis and highlights that the CDK control system operates within distinct regulatory domains in the nucleus and cytoplasm.

The Plus End-Directed Microtubule (Kinesin-3 Family) Motor Protein KIF13B Is Associated with the Photoreceptor Synaptic Ribbon Complex

2025-06-24

Shweta Suiwal , Karin Schwarz , Stephan Maxeiner +1 more | International Journal of Molecular Sciences

Retinal ribbon synapses are continuously active chemical synapses. The eponymous synaptic ribbon is anchored to the active zone neurotransmitter release sites of ribbon synapses, recruits synaptic vesicles and guides ribbon-associated … Retinal ribbon synapses are continuously active chemical synapses. The eponymous synaptic ribbon is anchored to the active zone neurotransmitter release sites of ribbon synapses, recruits synaptic vesicles and guides ribbon-associated synaptic vesicles to the release sites. RIBEYE is the major protein component of synaptic ribbons. But likely, additional proteins contribute to ribbon synapse function. The synaptic ribbon of photoreceptor synapses is embedded into a highly polarized microtubule cytoskeleton. Interestingly, proteins of the photoreceptor primary cilium, such as NPHP4 and other ciliary proteins, including KIF3A, were shown to be localized to photoreceptor synaptic ribbons. Previous studies demonstrated that the microtubule motor protein KIF13B catalyzes secretory vesicle transport to the plus ends of microtubules and identified an interaction of KIF13B with NPHP4 at primary cilia. However, the localization of KIF13B, a kinesin-3 family motor protein, in the retina is still unknown. In the present study, we used two different antibodies against KIF13B and high-resolution confocal microscopy, super-resolution structured illumination microscopy (SR-SIM), and post-embedding immunogold electron microscopy to determine the localization of KIF13B in retinal photoreceptors. Apart from its localization at the primary photoreceptor cilium, we found a strong enrichment of KIF13B at photoreceptor synaptic ribbons. The synaptic ribbon is needed for the synaptic enrichment of KIF13B as shown by analyses of synaptic ribbon-deficient RIBEYE knockout mice. These findings suggest that KIF13B performs vesicle trafficking functions at the photoreceptor synaptic ribbon complex at the interface between the synaptic ribbon and the presynaptic microtubule transport system.

HMMR/RHAMM recruits SACK1D/FAM83D-CK1α complex at the mitotic spindle to control spindle alignment

2025-06-24

Tyrell N. Cartwright , Naveen K. Nakarakanti , Karen J. Dunbar +5 more

Abstract The SACK1D/FAM83D-CK1α complex assembles at the mitotic spindle to orchestrate proper spindle positioning and error-free progression through mitosis. The full molecular picture of how this complex assembles and disassembles … Abstract The SACK1D/FAM83D-CK1α complex assembles at the mitotic spindle to orchestrate proper spindle positioning and error-free progression through mitosis. The full molecular picture of how this complex assembles and disassembles over the cell division cycle remains to be fully defined. Here, we show that HMMR is critical for SACK1D-CK1α complex formation at the spindle, co-localizes with the SACK1D-CK1α complex throughout mitosis, and is necessary for correct mitotic spindle alignment. We find that HMMR binds to the C-terminal α-helix of SACK1D, and this helix is also important for the mitotic interaction between SACK1D and CK1α. We demonstrate that HMMR binding stabilizes SACK1D. We map the mitotic hyperphosphorylation sites on SACK1D and show that this hyperphosphorylation signals the destruction of SACK1D upon mitotic exit. The destruction also requires the C-terminal α-helix of SACK1D, suggesting that hyperphosphorylation of SACK1D in mitosis potentially exposes the C-terminal degron sequences resident on SACK1D. This study provides key molecular insights into the assembly and fate of the HMMR-SACK1D-CK1α complex at the mitotic spindle.

Role of perinuclear microtubules in nuclear migration following cytokinesis of tobacco BY-2 cells

2025-06-24

Wataru Kurisu , Hiroki Yasuhara | CYTOLOGIA

Axonemal Dynein Visualized in Primary Cilia via Expansion Microscopy

2025-06-24

Xinhang Dong , Jung Hoon Cho , Jing W. Hughes | Cytoskeleton

Primary cilia are essential sensory organelles whose structural complexity has challenged detailed imaging analysis. Ultrastructure expansion microscopy (U-ExM) offers a promising approach by physically enlarging specimens in hydrogels, enabling nanoscale … Primary cilia are essential sensory organelles whose structural complexity has challenged detailed imaging analysis. Ultrastructure expansion microscopy (U-ExM) offers a promising approach by physically enlarging specimens in hydrogels, enabling nanoscale protein mapping. Here, we apply U-ExM to pancreatic islet cilia and demonstrate the conserved presence of all four axonemal dynein subtypes, including prominent localization of the intermediate chain DNAI1 in both primary cilia and centrioles. These findings suggest that U-ExM is a robust tool for ciliary studies and provide evidence that primary cilia may possess motor capabilities that could reshape our understanding of their function.

Codimension of jumping loci

2025-06-24

Brian Lehmann , Eric Riedl , Sho Tanimoto | Journal of Algebraic Geometry

Suppose that <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="script upper E"> <mml:semantics> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi class="MJX-tex-caligraphic" mathvariant="script">E</mml:mi> </mml:mrow> <mml:annotation encoding="application/x-tex">\mathcal {E}</mml:annotation> </mml:semantics> </mml:math> </inline-formula> is a vector bundle on a smooth projective … Suppose that <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="script upper E"> <mml:semantics> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi class="MJX-tex-caligraphic" mathvariant="script">E</mml:mi> </mml:mrow> <mml:annotation encoding="application/x-tex">\mathcal {E}</mml:annotation> </mml:semantics> </mml:math> </inline-formula> is a vector bundle on a smooth projective variety <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper X"> <mml:semantics> <mml:mi>X</mml:mi> <mml:annotation encoding="application/x-tex">X</mml:annotation> </mml:semantics> </mml:math> </inline-formula>. Given a family of curves <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper C"> <mml:semantics> <mml:mi>C</mml:mi> <mml:annotation encoding="application/x-tex">C</mml:annotation> </mml:semantics> </mml:math> </inline-formula> on <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper X"> <mml:semantics> <mml:mi>X</mml:mi> <mml:annotation encoding="application/x-tex">X</mml:annotation> </mml:semantics> </mml:math> </inline-formula>, we study how the Harder-Narasimhan filtration of <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="script upper E vertical-bar Subscript upper C Baseline"> <mml:semantics> <mml:mrow> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi class="MJX-tex-caligraphic" mathvariant="script">E</mml:mi> </mml:mrow> <mml:msub> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mo stretchy="false">|</mml:mo> </mml:mrow> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi>C</mml:mi> </mml:mrow> </mml:msub> </mml:mrow> <mml:annotation encoding="application/x-tex">\mathcal {E}|_{C}</mml:annotation> </mml:semantics> </mml:math> </inline-formula> changes as we vary <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper C"> <mml:semantics> <mml:mi>C</mml:mi> <mml:annotation encoding="application/x-tex">C</mml:annotation> </mml:semantics> </mml:math> </inline-formula> in our family. Heuristically we expect that the locus where the slopes in the Harder-Narasimhan filtration jump by <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="mu"> <mml:semantics> <mml:mi>μ</mml:mi> <mml:annotation encoding="application/x-tex">\mu</mml:annotation> </mml:semantics> </mml:math> </inline-formula> should have codimension which depends linearly on <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="mu"> <mml:semantics> <mml:mi>μ</mml:mi> <mml:annotation encoding="application/x-tex">\mu</mml:annotation> </mml:semantics> </mml:math> </inline-formula>. We identify the geometric properties which determine whether or not this expected behavior holds. We then apply our results to study rank <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="2"> <mml:semantics> <mml:mn>2</mml:mn> <mml:annotation encoding="application/x-tex">2</mml:annotation> </mml:semantics> </mml:math> </inline-formula> bundles on <inline-formula content-type="math/mathml"> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="double-struck upper P squared"> <mml:semantics> <mml:msup> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mi mathvariant="double-struck">P</mml:mi> </mml:mrow> <mml:mrow class="MJX-TeXAtom-ORD"> <mml:mn>2</mml:mn> </mml:mrow> </mml:msup> <mml:annotation encoding="application/x-tex">\mathbb {P}^{2}</mml:annotation> </mml:semantics> </mml:math> </inline-formula> and to study singular loci of moduli spaces of curves.

WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer

2025-06-23

Tomoaki Sobajima , Luke J. Fulcher , Caleb Batley +3 more | The EMBO Journal

Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell … Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.

Human fibroblasts from aged individuals exhibit chromosomal instability through replication stress caused by oxidative stress

2025-06-22

Kailin Zhu , Cheng Guan , Yuan Ren +2 more | bioRxiv (Cold Spring Harbor Laboratory)

Aneuploid cells are known to increase with age. Previously, we demonstrated that aneuploid cells increase in fibroblasts from aged mice due to chromosomal instability (CIN), which is caused by oxidative … Aneuploid cells are known to increase with age. Previously, we demonstrated that aneuploid cells increase in fibroblasts from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, which are more resistant to oxidative stress than mouse cells. Here, we found that fibroblasts from aged individuals exhibited an increase in aneuploid cells. The frequency of chromosome missegregation and micronuclei increased in these cells, indicating CIN. A DNA fiber assay revealed the presence of replication stress, accompanied by an increase in 53BP1 nuclear bodies and ultrafine bridges. Increased levels of reactive oxygen species derived from mitochondria, along with reduced mitochondrial membrane potential, imply that these cells experienced oxidative stress due to mitochondrial functional decline. Antioxidant treatment reduced the frequency of chromosome missegregation and micronuclei, suggesting that oxidative stress causes CIN. Oxidative stress also causes replication stress, which precedes CIN. Spindle microtubules were stabilized in fibroblasts from aged individuals, which was alleviated by antioxidant treatment. Taken together, these findings suggest that aging-related CIN in human fibroblasts is caused by oxidative stress associated with mitochondrial dysfunction, which induces replication stress that in turn causes CIN through microtubule stabilization. Although human fibroblasts are more resistant to the ambient oxygen environment than mouse fibroblasts, our findings showed that they undergo oxidative stress that causes CIN with age in a manner similar to mouse fibroblasts, revealing a conserved phenomenon in mammalian cells.

Neurogranin Unlocks the L-type Ca<sup>2+</sup>Channel and Directs Calmodulin Delivery

2025-06-21

Zhen Yu , Jinli Geng , Shuang Qiu +3 more | bioRxiv (Cold Spring Harbor Laboratory)

Neurogranin (Ng) is enriched in the postsynaptic density, with mounting evidence of its importance to neural pathophysiology. Ng has long been recognized as a dedicated calmodulin (CaM)-binding/buffering protein. This study … Neurogranin (Ng) is enriched in the postsynaptic density, with mounting evidence of its importance to neural pathophysiology. Ng has long been recognized as a dedicated calmodulin (CaM)-binding/buffering protein. This study demonstrates that Ng, through its CaM-binding IQ domain, directly binds the distal C-terminus (DCT) of the L-type Ca2+ (CaV1) channel, as a de novo mechanism regulating excitation-transcription coupling. The Ng/DCT interaction attenuates autonomous C-terminus-mediated inhibition and promotes specific CaM delivery to CaV1, cooperatively enhancing channel gating (activation and inactivation), Ca2+ influx and downstream neuronal signaling. Phosphorylation of Ng leads to the dissociation of the CaM C-lobe, while transiently forming the linkage with the CaM N-lobe. In contrast to neurodegenerative disease-related Ng mutants, WT Ng, within the above transient complex, enables the targeted CaM transfer to the proximal C-terminus of CaV1. Collective evidence from electrophysiology, binding assays, structural modeling and Ca2+ imaging supports a paradigm of dynamic intra- and inter-molecular interactions/facilitations underlying Ng and CaV1, both of which are representative CaM-binding proteins. This work proposes a mechanistic scheme potentially applicable to a broad scope of CaM-related physiology.

Aurora kinases signaling in cancer: from molecular perception to targeted therapies

2025-06-18

Prerna Vats , Camille Saini , Bhavika Baweja +4 more | Molecular Cancer

Aurora kinases, AURKA, AURKB, and AURKC, are serine/threonine kinases that play a vital role in regulating cell division and mitosis, particularly in the separation of chromosomes. These kinases are often … Aurora kinases, AURKA, AURKB, and AURKC, are serine/threonine kinases that play a vital role in regulating cell division and mitosis, particularly in the separation of chromosomes. These kinases are often overexpressed in human tumor cell lines, indicating their potential involvement in tumorigenesis. Preliminary evidence supports the use of Aurora kinase inhibitors for certain types of tumors, several AURKs inhibitors are currently under phase I and II trials. As a result, there is a growing interest in identifying small-molecule Aurora kinase inhibitors to develop as anti-cancer agents. The regulation of the cell cycle, including mitosis, is increasingly recognized as a key target in the fight against various forms of cancer. Novel drugs are being designed to inhibit the function of regulatory proteins, such as Aurora kinases, with the goal of creating personalized treatments. This review summarizes the biology of Aurora kinases in the context of cancer, integrating both preclinical and clinical data. It discusses the challenges and opportunities associated with using Aurora kinases to enhance cancer treatment. Future directions for Aurora kinase-based therapies include developing more selective inhibitors that minimize off-target effects and improve therapeutic efficacy. Researchers are also exploring combination therapies that use Aurora kinase inhibitors alongside other targeted treatments to overcome resistance and improve patient outcomes. Additionally, advancements in biomarker discovery are expected to facilitate the identification of patients most likely to benefit from Aurora kinase-targeted therapies, paving the way for more personalized approaches to cancer treatment.

The Luminal Ring Protein C2CD3 Acts as a Radial In-to-Out Organizer of the Distal Centriole and Appendages

2025-06-18

Éloïse Bertiaux , Vincent Louvel , Caitlyn L McCafferty +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Abstract Centrioles are polarized microtubule-based structures with appendages at their distal end that are essential for cilia formation and function. The protein C2CD3 is critical for distal appendage assembly, with … Abstract Centrioles are polarized microtubule-based structures with appendages at their distal end that are essential for cilia formation and function. The protein C2CD3 is critical for distal appendage assembly, with mutations linked to orofaciodigital syndrome and other ciliopathies. However, its precise molecular role in appendage recruitment remains unclear. Using Ultrastructure Expansion Microscopy (U-ExM), iterative U-ExM, and in situ cryo-electron tomography (cryo-ET), we reveal that C2CD3 adopts a radially symmetric 9-fold organization within the centriole’s distal lumen. We show that the C-terminal region of C2CD3 localizes close to a ∼100 nm luminal ring structure consisting of ∼27 nodes, while its N-terminal region localizes close to a hook-like structure that attaches to the A-microtubule as it extends from the centriole interior to exterior. This hook structure is adjacent to the DISCO complex (MNR/CEP90/OFD1), which marks future appendage sites. C2CD3 depletion disrupts not only the recruitment of the DISCO complex via direct interaction with MNR but also destabilizes the luminal ring network composed of C2CD3/SFI1/centrin-2/CEP135/NA14, as well as the distal microtubule tip protein CEP162. This reveals an intricate “in-to-out” molecular hub connecting the centriolar lumen, distal microtubule cap, and appendages. Although C2CD3 loss results in shorter centrioles and appendage defects, key structural elements remain intact, permitting continued centriole duplication. We propose that C2CD3 forms the luminal ring structure and extends radially to the space between triplet microtubules, functioning as an architectural hub that scaffolds the distal end of the centriole, orchestrating its assembly and directing appendage formation.

Estradiol pauses microtubule growth without increased incidence of catastrophe events

2025-06-18

Allison Ogren , Nicholas D. Zimmerman , Simone Stark +5 more | Communications Biology

Improved drug-screening tests of candidate anti-cancer drugs in patient-derived xenografts through use of numerous measures of tumor growth determined in multiple independent laboratories

2025-06-18

Elizabeth Rosenzweig , David Axelrod , Derek Gordon | PLoS ONE

Background Researchers screen candidate anti-cancer drugs for their ability to inhibit tumor growth in patient-derived xenografts (PDXs). Typically, a single laboratory will use a single measure of tumor growth. Purpose … Background Researchers screen candidate anti-cancer drugs for their ability to inhibit tumor growth in patient-derived xenografts (PDXs). Typically, a single laboratory will use a single measure of tumor growth. Purpose An effective drug-screening test as one that correctly identifies whether a drug treatment inhibits or does not inhibit tumor growth. We document improvements in the experimental design and statistical analysis of drug-screening tests based on the criteria of sensitivity and specificity. Methods We analyzed two published datasets. The response of each PDX model was known in advance. This information provided for statistical ground-truth classification. One dataset analyzed growth inhibition in the presence of one specific drug treatment for two PDX tumor models for numerous labs. A second dataset reported tumor growth of many PDX models in the presence of many drugs. A PDX model for which the treatment showed no tumor growth inhibition is referred to as Progressive Disease (PD). A PDX model for which the treatment showed complete tumor growth inhibition is referred to as Completely Responsive (CR). We created and analyzed four drug-screening tests, based on p-values for either a single-measure and single-lab, or p-values from meta-analysis and multiple-test correction. The outcome of each screening test was that either the drug treatment was effective or it was not. For both datasets, we computed median sensitivities and specificities by applying bootstrap resampling, and specification of a significance level. Results Our results showed that drug screening tests utilizing p-values from meta-analysis of numerous labs, or multiple test correction, produced median sensitivities and specificities that were always at least as high as those for the Single-Measure, Single-Lab test. This result was true for all significance levels. The 95% confidence intervals were usually greater in length for the Single-Measure, Single-Lab screening test.

Artificial Cells Evidence Apical Compressive Forces Building up During Neuroepithelial Organoid Early Development

2025-06-18

Hassan Kanso , Stefania Di Ciò , Ruth Rose +2 more | bioRxiv (Cold Spring Harbor Laboratory)

Abstract During early stages of development of cerebral organoids, budding neuroepithelia display striking changes in size and morphology, occurring very rapidly. Whilst mechanical forces mediated by cadherin-cadherin junctions are known … Abstract During early stages of development of cerebral organoids, budding neuroepithelia display striking changes in size and morphology, occurring very rapidly. Whilst mechanical forces mediated by cadherin-cadherin junctions are known to control the assembly, maturation and stability of epithelia, little is known of the mechanical context associated with neuroepithelial organoid development. In this report, we demonstrate a rapid translocation of YAP to budding neuroepithelial apical junctions, suggesting the build-up of strong compressive forces early on in their development. To study the mechanics of budding rosettes, we designed oil microdroplets stabilised by protein nanosheets displaying cadherin receptors, able to engage with receptors presented by neighbouring neuroepithelial cells, to integrate into embryoid bodies and developing organoids. The resulting artificial cells are able to sustain the formation of mature junctions with neighbouring cells and lead to the recruitment of tight junction maturation proteins such as ZO1. During early budding of neuroepithelial rosettes, artificial cells are found to be rapidly expelled from the developing organoids, further evidencing apical compressive forces. These forces are not opposed by sufficiently strong shear forces from neighbouring cells, or adhesive forces maintaining anchorage to the apical junction, to induce deformation of artificial cells.

How rogue jumping genes can spur Alzheimer’s, ALS

2025-06-17

Amber Dance | Knowable Magazine

Connectivity and Contraction in Cytoskeletal Networks

2025-06-16

Michael J. Norman , Annamarie Leske , Julio M. Belmonte | bioRxiv (Cold Spring Harbor Laboratory)

The cytoskeleton's ability to contract and propagate forces is the fundamental mechanism behind cell morphology, division and migration. This can only occur if the network is sufficiently connected, yet a … The cytoskeleton's ability to contract and propagate forces is the fundamental mechanism behind cell morphology, division and migration. This can only occur if the network is sufficiently connected, yet a rigorous description of the connectivity requirements has never been provided. In this work we focused on the polarity-sorting contraction mechanism and showed that connectivity is not determined by the spatial distribution of filaments alone, but by the interconnectivity between the dual network of filaments and motors. We developed a method to quantify filament-motor connectivity as a function of motor length, filament length distributions, and the densities of each component. Using this framework, we derived a general theory that predicts when a network is sufficiently connected to allow global or local contraction. We validated our predictions with computer simulations and introduced a novel metric to distinguish between these outcomes. Our findings show that the conditions for local and global contraction in the presence of fiber dynamics correspond, respectively, to the pulsatile and steady-state contraction behaviors observed in vivo. All results are independent of filament rigidity, making our conclusions applicable to both actin and microtubule networks. Lastly, we discuss how those outcomes are affected by the introduction of crosslinking proteins, which - despite not actively generating forces of their own - can promote global contractility at small concentrations even in networks made of short and/or rigid filaments.

Confinement in fibrous environments positions and orients mitotic spindles

2025-06-16

Apurba Sarkar , Aniket Jana , Atharva Agashe +6 more | PNAS Nexus

Abstract Accurate positioning of the mitotic spindle within the rounded cell body is critical to physiological maintenance. Mitotic cells encounter confinement from neighboring cells or the extracellular matrix (ECM), which … Abstract Accurate positioning of the mitotic spindle within the rounded cell body is critical to physiological maintenance. Mitotic cells encounter confinement from neighboring cells or the extracellular matrix (ECM), which can cause rotation of mitotic spindles and tilting of the metaphase plate (MP). To understand the effect of confinement on mitosis by fibers (ECM confinement), we use flexible ECM-mimicking nanofibers that allow natural rounding of the cell body while confining it to differing levels. Rounded mitotic bodies are anchored in place by actin retraction fibers (RFs) originating from adhesions on fibers. We discover that the extent of confinement influences RF organization in 3D, forming triangular and band-like patterns on the cell cortex under low and high confinement, respectively. Our mechanistic analysis reveals that the patterning of RFs on the cell cortex is the primary driver of the MP rotation. A stochastic Monte-Carlo simulation of the centrosome (CS), chromosome (CH), membrane interactions, and 3D arrangement of RFs recovers MP tilting trends observed experimentally. Under high ECM confinement, the fibers can mechanically pinch the cortex, causing the MP to have localized deformations at contact sites with fibers. Interestingly, high ECM confinement leads to low and high MP tilts, which we mechanistically show to depend upon the extent of cortical deformation, RF patterning, and MP position. We identify that cortical deformation and RFs work in tandem to limit MP tilt, while asymmetric positioning of MP leads to high tilts. Overall, we provide fundamental insights into how mitosis may proceed in ECM-confining microenvironments in vivo.

Cell cycle dependent methylation of Dam1 contributes to kinetochore integrity and faithful chromosome segregation

2025-06-16

Prashant Mishra , Wei-Chun Au , John S. Choy +7 more | PLoS Genetics

The kinetochore, a megadalton structure composed of centromeric ( CEN ) DNA and protein complexes, is required for faithful chromosome segregation in eukaryotes. The evolutionarily conserved Dam1/DASH complex (Ska1 in … The kinetochore, a megadalton structure composed of centromeric ( CEN ) DNA and protein complexes, is required for faithful chromosome segregation in eukaryotes. The evolutionarily conserved Dam1/DASH complex (Ska1 in metazoans) is one of the essential protein sub-complexes of the budding yeast kinetochore. Previous studies showed that methylation of lysine residue 233 in Dam1 by Set1 is important for haploid growth as mutation of lysine 233 to alanine results in lethality. In this study, we report that Set1-mediated cell cycle dependent Dam1 lysine methylation contributes to kinetochore assembly and chromosomal stability. Our results show that Dam1 methylation is cell cycle regulated with the highest levels of methylation in metaphase. Consistent with these results, co-immunoprecipitation experiments revealed an interaction between Dam1 with Set1 in metaphase cells. Set1 has been shown to colocalize with Jhd2, a histone lysine demethylase which demethylates Set1-methylated histones. Affinity purification-based mass spectroscopy of Jhd2 associated proteins identified seven of the ten subunits of the Dam1 complex; an association of Jhd2 with non-histone proteins, such as Dam1 has not been previously reported. We confirmed the interaction of Jhd2 with Dam1 and showed that cells overexpressing JHD2 exhibit reduced levels of methylated lysine in Dam1 in wild type and UBP8 deletion strains, growth defects in kinetochore mutants, reduced levels of kinetochore proteins at CEN chromatin, defects in kinetochore biorientation and chromosome missegregation. In summary, we have shown that cell cycle dependent methylation of Dam1 plays a crucial role in the maintenance of kinetochore assembly for faithful chromosome segregation.

Nuances in the control of separase activity between mitosis and meiosis

2025-06-16

Martin Anger | PLoS Biology

Mammalian oocytes are prone to chromosome segregation errors, which frequently lead into aneuploidy and pregnancy loss. A new study in PLOS Biology addresses the role of the Mad2/SGO2 complex in … Mammalian oocytes are prone to chromosome segregation errors, which frequently lead into aneuploidy and pregnancy loss. A new study in PLOS Biology addresses the role of the Mad2/SGO2 complex in the control of separase activity in these cells during meiosis.

<scp>LZTS2</scp> Negatively Regulates Centrosomal <scp>CEP135</scp> Levels and Microtubule Nucleation

2025-06-16

Catarina Peneda , Joana N. Bugalhão , Marco António Dias Louro +2 more | Cytoskeleton

ABSTRACT The microtubule cytoskeleton is a fundamental functional component of the cell. In vertebrate proliferating cells, centrosomes are the primary microtubule organizing center (MTOC), and their dysregulation has been linked … ABSTRACT The microtubule cytoskeleton is a fundamental functional component of the cell. In vertebrate proliferating cells, centrosomes are the primary microtubule organizing center (MTOC), and their dysregulation has been linked to genomic instability and cancer. LZTS2, a known tumor suppressor, localizes to centrosomes and regulates microtubule severing. However, whether LZTS2 regulates centrosome structure and/or its function in microtubule organization or ciliation remains unknown. Here, we investigate the function of LZTS2 at the centrosome. Through fluorescence and electron microscopy assays, we observed that LZTS2 knockdown does not affect centriole biogenesis or structure, nor ciliation. Importantly, we show that LZTS2 depletion increases microtubule nucleation at the centrosome. Moreover, LZTS2 negatively regulates centrosomal levels of CEP135. Notably, depletion of LZTS2 can partially rescue the impaired centrosome microtubule nucleation caused by CEP135 knockdown. Taken together, our findings reveal a novel role for LZTS2 as a negative regulator of CEP135 and centrosomal microtubule nucleation, providing a potential mechanistic link to its tumor suppressor function.

Mitotic BLM functions are required to maintain genomic stability

2025-06-16

Tamara Eleanore Hamann , Angela Wieland , Andrea Tirincsi +7 more | bioRxiv (Cold Spring Harbor Laboratory)

The BLM helicase is a critical genome maintenance protein involved in diverse cellular processes including DNA replication, repair, transcription, and chromosome segregation. During mitosis, it cooperates with the PICH helicase … The BLM helicase is a critical genome maintenance protein involved in diverse cellular processes including DNA replication, repair, transcription, and chromosome segregation. During mitosis, it cooperates with the PICH helicase and topoisomerases to resolve ultrafine DNA bridges (UFBs) - non-chromatinized DNA structures that link sister chromatids - through a mechanism that is not yet fully understood. Here we tagged endogenous BLM and PICH with fluorescent proteins and BLM with an auxin-inducible degron to generate a cell model system that enables temporal tracking of UFB dynamics in the presence or absence of BLM. Time-resolved lattice light sheet microscopy established the dynamic localization patterns of BLM and PICH throughout the cell cycle. While BLM cycles between PML bodies and DNA repair foci in interphase, it dissociates from chromatin at the mitotic entry, and re-associates during anaphase to UFBs as well as to CENP-B-positive mitotic foci. Acute BLM depletion during mitosis increased the fraction of unresolved UFBs, micronuclei containing acentric fragments, binucleation, and resulted in subtle genomic abnormalities detected by single-cell whole genome sequencing. These findings highlight a mitosis-specific role for BLM in UFB resolution and underscore its function in preserving genomic stability.

Defining the polycystin pharmacophore through high-throughput screening and computational biophysics.

2025-06-15

Eduardo Guadarrama , Carlos G Vanoye , Paul G. DeCaen | PubMed

Polycystins (PKD2, PKD2L1) are voltage-gated and Ca2+-modulated members of the TRP family of ion channels. Loss of PKD2L1 results in seizure-susceptibility and autism-like features in mice, whereas variants in PKD2 … Polycystins (PKD2, PKD2L1) are voltage-gated and Ca2+-modulated members of the TRP family of ion channels. Loss of PKD2L1 results in seizure-susceptibility and autism-like features in mice, whereas variants in PKD2 cause autosomal dominant polycystic kidney disease. Despite decades of evidence demonstrating their physiological importance in the brain and kidneys and linking their dysfunction to human disease, the polycystin pharmacophore remains undefined. Contributing to this knowledge gap is their resistance to drug screening campaigns, which are hindered by the unique subcellular trafficking of these channels to organelles such as the primary cilium. PKD2L1 is the only member of the polycystin family to form constitutively active ion channels in the plasma membrane when overexpressed. HEK293 cells stably expressing PKD2L1 F514A were screened pharmacologically via high-throughput electrophysiology to identify potent polycystin channel modulators. In silico docking analysis and mutagenesis were used to define the receptor sites of screen hits. Inhibition by membrane-impermeable QX-314 was used to evaluate PKD2L1-binding site accessibility. Screen results identify potent PKD2L1 inhibitors with divergent chemical core structures and highlight striking similarities between the molecular pharmacology of PKD2L1 and voltage-gated sodium channels. Docking analysis, channel mutagenesis and electrophysiological recordings identify an open-state accessible lateral fenestration receptor within the pore and a mechanism of inhibition that stabilises the PKD2L1 inactivated state. Outcomes establish the suitability of our approach to expand our chemical knowledge of polycystins and delineate novel receptor moieties for the development of channel-specific inhibitors in TRP channel research.

Kinetic asymmetry drives kinesin-1's unidirectional and processive movement

2025-06-15

Hiroshi Isojima , Kohei Matsuzaki , Michio Tomishige | bioRxiv (Cold Spring Harbor Laboratory)

Kinesin-1 is a dimeric motor protein that uses ATP hydrolysis energy to move along microtubules in a hand-over-hand manner. The unidirectional movement of kinesin-1 has traditionally been explained by an … Kinesin-1 is a dimeric motor protein that uses ATP hydrolysis energy to move along microtubules in a hand-over-hand manner. The unidirectional movement of kinesin-1 has traditionally been explained by an ATP-dependent power stroke action of the neck linker, connecting its two catalytic domains (heads), that biases the diffusional motion forward (biased-diffusion). However, recent studies on synthetic molecular motors have supported a Brownian ratchet mechanism based on kinetic asymmetry between two locations (biased-binding), and which of these mechanisms applies to biological motors remains debated. Here, we engineered a two-headed kinesin that alternately uses these mechanisms to step forward, allowing us to investigate how they contribute to unidirectional movement. The tethered head that uses biased-diffusion frequently rebound to the rear-binding site but eventually stepped forward, as the front head remained securely bound to the microtubule. The biased-binding mechanism proved more efficient by preventing rebinding of the detached head and was independent of ATP binding. Instead, ATP hydrolysis energy is primarily consumed to ensure preferential detachment of the rear head. These findings demonstrate that kinesin-1 functions as an information ratchet based on kinetic asymmetry in microtubule-binding and detachment of the heads, while power strokes serve to enhance movements under load.

MEIOC prevents continued mitotic cycling and promotes meiotic entry during mouse oogenesis

2025-06-15

Esther G. Ushuhuda , Joseph Nguyen , Natalie G. Pfaltzgraff +2 more | bioRxiv (Cold Spring Harbor Laboratory)

In multicellular organisms, germ cells' transformation into haploid gametes requires that they transition from mitosis to meiosis, whereby they stop mitotic cycling and enter the meiotic cell cycle. In mammals, … In multicellular organisms, germ cells' transformation into haploid gametes requires that they transition from mitosis to meiosis, whereby they stop mitotic cycling and enter the meiotic cell cycle. In mammals, transcriptional activator STRA8-MEIOSIN mediates the decision to enter the meiotic cell cycle by triggering the G1-to-meiotic S phase transition. However, the molecular basis by which mammalian germ cells prevent continued mitotic cycling before entering the meiotic cell cycle remains unclear. Here, we investigate MEIOC's role in the mitosis-to-meiosis transition during mouse oogenesis by analyzing proliferation, cell cycle transcriptomics, and cell cycle-associated protein expression. MEIOC was previously shown to destabilize mRNA and repress the mitotic program after meiotic entry. Here, we demonstrate that MEIOC prevents continued mitotic cycling prior to meiotic entry in oogenic cells. We find that the mitosis-to-meiosis transition involves the repression of G1/S cyclin CCNA2 at the transcript and protein levels, and that MEIOC downregulates CCNA2 protein expression. In addition, MEIOC promotes entry into meiotic S phase by increasing Meiosin transcript abundance and consequently activating the STRA8-MEIOSIN transcription factor. Given that STRA8-MEIOSIN upregulates Meioc expression, MEIOC and STRA8-MEIOSIN form a positive feedback loop to reinforce timely meiotic initiation. We also demonstrate that BMP signaling halts mitotic cycling and promotes meiotic entry by upregulating MEIOC. We conclude that, in mouse oogenic cells, the transition from mitosis to meiosis occurs as two molecularly regulated steps - (i) halt of mitotic cycling and (ii) entry into the meiotic cell cycle - and that MEIOC modifies the cell cycle program to facilitate both steps in this transition.

Collision of solitons in neuronal microtubules with dipole–dipole interaction

2025-06-13

Yaseen M. Lone , E. Parasuraman | Alexandria Engineering Journal

Phosphorylation-inducing chimera rewires oncogenic kinase to trigger apoptosis

2025-06-13

Maximilian Merz , Veronika M. Shoba , Rajaiah Pergu +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Hyperactive enzymes drive the pathology of several diseases, and classically, ″occupancy-driven″ drugs (e.g., active site or allosteric inhibitors) are used to target these enzymes. However, the stoichiometric nature of such … Hyperactive enzymes drive the pathology of several diseases, and classically, ″occupancy-driven″ drugs (e.g., active site or allosteric inhibitors) are used to target these enzymes. However, the stoichiometric nature of such inhibitors and the emergence of resistance highlight the need for new modalities. Here, we report a Phosphorylation-Inducing Chimeric Small molecule (PHICS) that rewires the hyperactivity of an oncogenic kinase, BCR-ABL, to phosphorylate its active site residue. Molecular dynamics simulations suggest this phosphorylation inhibits BCR-ABL by inducing electrostatic rearrangements of its active site. This ″event-driven″ mechanism selectively induces apoptosis of BCR-ABL-dependent cancer cells at substoichiometric concentrations (vs. stoichiometric concentrations of occupancy-driven drugs). Furthermore, PHICS is effective on other oncogenic ABL fusions or clinically observed resistance mutations, including to occupancy-driven drugs with the same binding site as PHICS, pointing to the orthogonality of their resistance mechanisms. These studies lay the foundation for electric-field and ″event-driven″ modalities to control hyperactive enzymes with orthogonal resistance mechanisms to occupancy-driven modalities.

Abstract P4-05-09: ERIBULIN'S ARCANE ODYSSEY: UNRAVELING STEVEN JOHNSON SYNDROME (SJS) /TOXIC EPIDERMAL NECROLYSIS (TEN) IN METASTATIC BREAST CANCER

2025-06-13

Arti Goel , Sudeep Gupta , Prabhat Bhargava +5 more | Clinical Cancer Research

Abstract Abstract: Eribulin mesylate is a non-taxane inhibitor of microtubule dynamics belonging to the halichondrin class of antineoplastic drugs. It is a novel agent that inhibits the microtubule growth phase … Abstract Abstract: Eribulin mesylate is a non-taxane inhibitor of microtubule dynamics belonging to the halichondrin class of antineoplastic drugs. It is a novel agent that inhibits the microtubule growth phase without affecting the shortening phase, causing tubulin sequestration into non-productive aggregates. Eribulin is used as monotherapy in heavily treated metastatic breast cancer patients resistant to taxane or anthracycline-based chemotherapy. Common Grade 3 or 4 adverse events with Eribulin include neutropenia (52%), leucopenia (23%), thrombocytopenia (19%), and peripheral neuropathy (35%). Cutaneous manifestations with Eribulin are uncommon. However, Steven Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) is a rare and severe mucocutaneous reaction characterized by extensive necrosis and detachment of the epidermis, often triggered by medications. Here we present a case of SJS/TEN caused by Eribulin in a woman with Metastatic Breast cancer. Introduction: A 55-year-old post-menopausal hypothyroid woman was diagnosed with triple-negative breast cancer (TNBC) with metastasis to the liver and non-regional nodes. She was found to be refractory to anthracycline, docetaxel, capecitabine, and platinum agents and was thus planned for Eribulin monotherapy as a third-line agent. On day 11 of Cycle 1 of Eribulin at 1.4 mg/m2, she presented with high-grade fever and a rash over her torso and arms, which gradually spread to approximately 80% of her body surface area. Further examination revealed Grade 2 oral mucositis as per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The rash initially presented as targetoid lesions involving the torso and then gradually covered up to 80% of the body surface area, sparing the scalp. Later, the rash became confluent and formed flaccid bullae, but the Nikolsky sign was negative. She had a persistent high-grade fever with temperatures reaching up to 104°F. All infective workup evaluations were negative. Her lab parameters suggested Grade 2 transaminitis, Grade 2 hypokalaemia, and hyponatremia as per CTCAE v5.0. Blood culture and swab culture from the skin lesions were negative. She was non-neutropenic throughout the course. A skin punch biopsy of the largest lesion on her back showed trans-epidermal neutrophilic infiltration, suggestive of a drug-induced hypersensitivity reaction. Ruling out other infective etiologies and considering the temporal relationship between initiating Eribulin therapy and the development of the rash, she was clinically diagnosed with Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN). Further probing confirmed that her drug history did not indicate any alternative medications intake. Due to persistent high-grade fever, she was started on empirical antibiotics, meropenem, and teicoplanin. As there was no clinical improvement over 24 hours, she was started on dexamethasone at 24 mg/day. Over 15 days, with gradual tapering, her skin lesions healed by more than 75% from baseline. She was discharged in a hemodynamically stable condition. On her first follow-up visit after 15 days, her lesions had healed, with mild hyperpigmentation persisting over her face and arms. Conclusion: SJS/TEN is a life-threatening mucocutaneous reaction that typically is not associated with chemotherapy. We present a case of SJS/TEN where the drug eribulin was identified as the causative agent. Despite the high mortality rate of TEN (&gt;30%), our patient successfully recovered, likely due to the prompt recognition of the syndrome, immediate discontinuation of the causative drug, and timely treatment with steroids. This case underscores the critical importance of considering SJS/TEN in any patient presenting with an extensive, desquamative rash following eribulin chemotherapy. Quick intervention can be the difference between life and death, highlighting the need for vigilance and rapid response in managing adverse drug reactions. Citation Format: Arti Goel, Sudeep Gupta, Prabhat Ghanshyam Bhargava, Seema Gulia, Sushmitha Rath, Shalaka Joshi, Tabassum Wadasadawala, Dileep Hoysal. ERIBULIN'S ARCANE ODYSSEY: UNRAVELING STEVEN JOHNSON SYNDROME (SJS) /TOXIC EPIDERMAL NECROLYSIS (TEN) IN METASTATIC BREAST CANCER [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-05-09.

Role of PLK4 inhibition in cancer therapy

2025-06-13

Kishore Banik , Thomas J. Hayman | Cancer and Metastasis Reviews

CLASP1 regulates Dynein for PLK1-mediated spindle organization and cytokinesis in oocyte meiosis

2025-06-12

Meng‐Meng Shan , Ping‐Shuang Lu , Yuanjing Zou +4 more | Journal of Cell Science

The meiotic spindle organization and cytokinesis are important for mammalian oocyte maturation. CLIP-associating protein (CLASP) 1 is a member of microtubule plus-end binding proteins, which is reported to regulate cytokinesis … The meiotic spindle organization and cytokinesis are important for mammalian oocyte maturation. CLIP-associating protein (CLASP) 1 is a member of microtubule plus-end binding proteins, which is reported to regulate cytokinesis in mitosis; however, the functions of CLASP1 in meiosis are still unclear. In this study, we reported that CLASP1 played critical roles both at metaphase and telophase in mouse oocyte meiosis. Our results indicated that CLASP1 was essential for oocyte maturation and its depletion caused the spindle organization and microtubule-kinetochore attachment defects at metaphase Ⅰ, while this might be due to its association with PLK1/p-MAPK. Besides, deacetylases HDAC6/ SIRT1 were found to be decreased which further affected tubulin acetylation level and microtubule stability after CLASP1 depletion. We also showed that CLASP1 could associate with PLK1/PRC1-based central spindle formation and cytokinesis at telophase Ⅰ. Moreover, Dynein was recognized to interact closely with CLASP1 and may function as a downstream motor protein involved in the orderly transport of PLK1. Taken together, we demonstrated that CLASP1 may play multiple roles in Dynein-based PLK1 for spindle organization and cytokinesis in mouse oocyte meiosis.

In silico molecular studies of Phosphinogold(I) thiocarbohydrate complexes: insights into multi-target anticancer mechanisms

2025-06-12

Alaa A. Mohamed , Isaac Asiamah , Ghazi Elamin +2 more | Frontiers in Chemistry

Introduction: This study employed in silico methods to investigate the anticancer potential and mechanisms of twenty novel phosphinogold(I) thiocarbohydrate complexes. Methods: Molecular docking and Prime MM-GBSA screening of seventeen cancer-related … Introduction: This study employed in silico methods to investigate the anticancer potential and mechanisms of twenty novel phosphinogold(I) thiocarbohydrate complexes. Methods: Molecular docking and Prime MM-GBSA screening of seventeen cancer-related protein targets, including Human Double Minute 2 protein (HDM2), DNA methyltransferase-1 (DNMT1), Protein Kinase B (AKT2), and Poly (ADP-ribose) polymerase 1 (PARP-1), were conducted. Molecular dynamics simulations were performed for complex 9 . Results: Virtual screening revealed strong binding affinities for several complexes, often surpassing native ligands. All the complexes except 16 , 18 , and 19 exhibited strong binding affinity with one or two cancer protein targets compared to native ligands. Complex 9 emerged as the best candidate, demonstrating promising binding affinity particularly against AKT2 (–82.40 kcal/mol) and PARP-1 (–75.7 kcal/mol). Molecular dynamics simulations of complex 9 with PARP-1 and AKT2 revealed distinct binding profiles, with a more stable interaction with PARP-1, suggesting its potential for disrupting DNA repair mechanisms. Binuclear complexes generally exhibited higher affinities than mononuclear counterparts, particularly for DNMT1 and HDM2. Complex 13 demonstrated high in vitro activity against prostate, colon, and breast cancer cell lines (IC50 = 0.03, 0.25, and 0.07 μM respectively), collaborating with a significant interaction with Human Epidermal Growth Factor Receptor 2 (HER2) (–71.15 kcal/mol binding affinity) in silico . While acetylation decreased binding affinity; it enhanced cellular activity as reported in in vitro studies indicative of the need to balance lipophilicity and binding strength in future ligand design. Discussion: These findings provide valuable insights into multi-target anticancer mechanisms, with a particular emphasis on complex 9 as a potential PARP-1 inhibitor, and guide future optimization and experimental validation of these novel gold-based complexes. The stable interaction of complex 9 with PARP-1 highlights PARP-1 as a particularly promising therapeutic target. Binuclear complexes' superior affinities for DNMT1 and HDM2 suggest structural advantages for multi-target inhibition. Conclusion: The paradoxical effect of acetylation underscores the importance of balancing lipophilicity and binding strength in ligand design.

Microtubules

2025-06-11

Anca Dragomir | CRC Press eBooks