scholarly journals Mathematical Modeling of Effect Of Microtubule-Targeted Agents On Microtubule Dynamic Instability

2018 ◽  
Vol 62 ◽  
pp. 1-16
Author(s):  
Ayuna Barlukova ◽  
Stéphane Honoré ◽  
Florence Hubert
Keyword(s):  
Mathematical Modeling ◽  
Dynamic Instability ◽  
Growth Speed ◽  
Model Parameters ◽  
Cancer Cell Migration ◽  
Targeted Agents ◽  
Potential Mechanism ◽  
Microtubule Dynamic ◽  
Drug Concentrations ◽  
Param Eters

Microtubule-targeted agents (MTAs), widely used in chemotherapy, are molecules that are able to block cancer cell migration and division. Their effect on microtubule (MT) dynamic instability is measured by their influence on observable parameters of MT dynamics such as growth speed, time-based catastrophe frequency, time-based rescue fre- quency, etc. In this paper, we propose a new mathematical model that is able to reproduce MT dynamics with an appropriate estimation of the main observable parameters. Using the experimental data on paclitaxel effect in presence of EB proteins, we fitted param- eters of the model from several drug concentrations. It enable us to understand which non-observable model parameters are able to reproduce the effect of MTAs and thus to highlight a new potential mechanism of action associated with MTAs effect in presence of EB protein.

Mathematical modeling of microtubule dynamic instability: new insight into the link between gtp-hydrolysis and microtubule aging

2018 ◽  
Vol 52 (6) ◽  
pp. 2433-2456 ◽  
Author(s):  
Ayuna Barlukova ◽  
Diana White ◽  
Gérard Henry ◽  
Stéphane Honoré ◽  
Florence Hubert
Keyword(s):  
Dynamic Instability ◽  
Dynamic Properties ◽  
Model Parameters ◽  
Microtubule Dynamic ◽  
Gtp Hydrolysis ◽  
Unique Type ◽  
Microtubule Targeting Agents ◽  
Age Dependent ◽  
Type Of Behavior ◽  
Insight Into

Microtubules (MTs) are protein polymers that exhibit a unique type of behavior referred to as dynamic instability. That is, they undergo periods of growth (through the addition of GTP-tubulin) and shortening (through the subtraction of GDP-tubulin). Shortening events are very fast, where this transition is referred to as a catastrophe. There are many processes that regulate MT dynamic instability, however, recent experiments show that MT dynamics may be highly regulated by a MTs age, where young MTs are less likely to undergo shortening events than older ones. In this paper, we develop a novel modeling approach to describe how the age of a MT affects its dynamic properties. In particular, we extend on a previously developed model that describes MT dynamics, by proposing a new concept for GTP-tubulin hydrolysis (the process by which newly incorporated GTP-tubulin is hydrolyzed to lower energy GDP-tubulin). In particular, we assume that hydrolysis is mainly vectorial, age-dependent and delayed according to the GTP-tubulin incorporation into the MT. Through numerical simulation, we are able to show how MT age affects certain properties that define MT dynamics. For example, simulations illustrate how the aging process leads to an increase in the rate of GTP-tubulin hydrolysis for older MTs, as well as increases in catastrophe frequency. Also, since it has been found that MT dynamic instability is affected by chemotherapy microtubule-targeting agents (MTAs), we highlight the fact that our model can be used to investigate the action of MTAs on MT dynamics by varying certain model parameters.

scholarly journals Dock5 is a new regulator of microtubule dynamic instability through GSK3β inhibition in osteoclasts

2019 ◽  
Author(s):  
Sarah Guimbal ◽  
David Guérit ◽  
Manon Chardon ◽  
Anne Blangy ◽  
Virginie Vives
Keyword(s):  
Dynamic Instability ◽  
Direct Interaction ◽  
Background Information ◽  
Growth Speed ◽  
Microtubule Dynamic ◽  
Zone Formation ◽  
Acetylated Tubulin ◽  
Bone Degradation ◽  
Sealing Zone ◽  
Osteoclast Resorption

AbstractBackground informationOsteoclast resorption is dependent on a podosome-rich structure, called sealing zone, which is stabilized by acetylated microtubules. It tightly attaches the osteoclast to the bone creating a favorable acidic microenvironment for bone degradation. We already established that Rac activation by Dock5 is necessary for osteoclast resorption. Indeed, inhibition of Dock5 in osteoclasts results in Rac1 decreased activity associated to impaired podosome assembly into sealing zones and resorbing activity.ResultsIn this report, we show that Dock5 knockout osteoclasts also present a reduced acetylated tubulin level leading to a decreased length and duration of microtubule growth phases whereas their growth speed remains unaffected. Dock5 does not act by direct interaction with the polymerized tubulin but through inhibition of the microtubules destabilizing kinase GSK3β downstream of Akt activation. Interestingly, we ruled out the implication of Rac1 in this process using specific inhibitors.ConclusionOur data involve Dock5 as a new regulator of microtubule dynamic instability in osteoclast.SignificanceThe fact that Dock5 is a regulator of both actin cytoskeleton and microtubule dynamics makes it an interesting therapeutic target for osteolytic pathologies because of its dual role on sealing zone formation and stabilization.

Analysis of the Mechanism of Microtubule Dynamic Instability Using a UV Microbeam to Sever Elongating Microtubules

1988 ◽  
Vol 46 ◽  
pp. 122-123
Author(s):  
R.A Walker ◽  
S. Inoue ◽  
E.D. Salmon
Keyword(s):  
Dynamic Instability ◽  
Microtubule Dynamic ◽  
Gtp Hydrolysis ◽  
Abrupt Transition ◽  
Microtubule Associated Proteins ◽  
Asymmetrical Structure ◽  
Associated Proteins

Microtubules polymerized in vitro from tubulin purified free of microtubule-associated proteins exhibit dynamic instability (1,2,3). Free microtubule ends exist in persistent phases of elongation or rapid shortening with infrequent, but, abrupt transitions between these phases. The abrupt transition from elongation to rapid shortening is termed catastrophe and the abrupt transition from rapid shortening to elongation is termed rescue. A microtubule is an asymmetrical structure. The plus end grows faster than the minus end. The frequency of catastrophe of the plus end is somewhat greater than the minus end, while the frequency of rescue of the plus end in much lower than for the minus end (4).The mechanism of catastrophe is controversial, but for both the plus and minus microtubule ends, catastrophe is thought to be dependent on GTP hydrolysis. Microtubule elongation occurs by the association of tubulin-GTP subunits to the growing end. Sometime after incorporation into an elongating microtubule end, the GTP is hydrolyzed to GDP, yielding a core of tubulin-GDP capped by tubulin-GTP (“GTP-cap”).

scholarly journals Temperature-jump studies of microtubule dynamic instability.

1988 ◽  
Vol 263 (21) ◽  
pp. 10344-10352
Author(s):  
M Caplow ◽  
J Shanks ◽  
R L Ruhlen
Keyword(s):  
Temperature Jump ◽  
Dynamic Instability ◽  
Microtubule Dynamic

scholarly journals Motile kinetochores and polar ejection forces dictate chromosome position on the vertebrate mitotic spindle

1994 ◽  
Vol 124 (3) ◽  
pp. 223-233 ◽  
Author(s):  
CL Rieder ◽  
ED Salmon
Keyword(s):  
Mitotic Spindle ◽  
Constant Velocity ◽  
Molecular Mechanisms ◽  
Dynamic Instability ◽  
Microtubule Dynamic ◽  
Pole Motion ◽  
Microtubule Motors ◽  
Chromosome Position ◽  
Pulling Forces

We argue that hypotheses for how chromosomes achieve a metaphase alignment, that are based solely on a tug-of-war between poleward pulling forces produced along the length of opposing kinetochore fibers, are no longer tenable for vertebrates. Instead, kinetochores move themselves and their attached chromosomes, poleward and away from the pole, on the ends of relatively stationary but shortening/elongating kinetochore fiber microtubules. Kinetochores are also "smart" in that they switch between persistent constant-velocity phases of poleward and away from the pole motion, both autonomously and in response to information within the spindle. Several molecular mechanisms may contribute to this directional instability including kinetochore-associated microtubule motors and kinetochore microtubule dynamic instability. The control of kinetochore directional instability, to allow for congression and anaphase, is likely mediated by a vectorial mechanism whose magnitude and orientation depend on the density and orientation or growth of polar microtubules. Polar microtubule arrays have been shown to resist chromosome poleward motion and to push chromosomes away from the pole. These "polar ejection forces" appear to play a key role in regulating kinetochore directional instability, and hence, positions achieved by chromosomes on the spindle.

scholarly journals Regulation of Mitotic Microtubule Dynamic Instability in Monopolar Spindles by Bundling and Kinetochore Attachment

2017 ◽  
Vol 31 (S1) ◽  
Author(s):  
Zachary R Gergely ◽  
Patrick J Flynn ◽  
Salvador Montes ◽  
J. Richard McIntosh ◽  
M. D. Betterton
Keyword(s):  
Dynamic Instability ◽  
Microtubule Dynamic
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