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PubMed1997

[Multidrug resistance (MDR) in oncology].

Multidrug resistance or mdr is a frequent phenomenon for which tumor cells can develop, in only one step, cross-resistance to a different anticancer drugs such as antibiotics, vinca alkaloids and podophylotoxins. This is due to an extrusion of drugs out of the cells, since it is interrelated with the decrease of the intracellular concentration of the drug, compared to sensitive cells. This phenomeno of multidrug resistance (mdr) is considered one of the principal causes of failure in quimiotherapic treatment of cancer, and is associated in many cases to an hyperexpression of mdr-I gene, that codifies for a high molecular weight glycoprotein (p-170) (170-180 Kdaltons), also called p-glycoprotein (pgp). Locadet it in the cellular membrane extracts, like a pump, the quimiotherapic drugs with consumption of ATP. In humans, there are two principal genes that codify for pgp: mdr-I and mdr2/3; being the most important the mdr-I gene. The structure of p-glycoprotein consists in two symmetrical halves anchored in the cellular membrane that includes three extracellular dominances each one, and on intracellular portion with the ATP binding site. Also, has got an for extracellular carbohydrates chain. It is specially important to find drugs that reverse the multidrug resistance. Chemicals such as verapamil, nifedine, quinidine and calmodulin inhibitors are joined to pgp inhibiting it. A Cyclosporine and its non-immunosuppressors derivateds such as SDZ 280-125 and SDZ PSC 833 reverse mdr. At present it is being advancing in clinical trials, but the results are not satisfactory. Most useful chemicals are verapamil, better R-verapamil and A-cyclosporine or its non-immunosuppressors derivates. Futures possibilities are grateful. From diagnostic point of view the mains are: 1. Detection of mdr-I gene. 2. Recognition of the presence of mRNA for pgp. 3. Detection of pgp by flow cytometry or western blot. 4. Immunohistochemistry with monoclonal antibodies to pgp. 5. Rhodamine 123 to study mdr phenotype. 6. Multidrug resistance modulators in vitro. 7. pgp in vivo as a tumor marker. From therapeutic point of view: 1. To assay mdr modulators with higher power and better tolerated. 2. Reversing of mdr with in vivo MoAbs and/or immunotoxins. 3. Gene therapy. 4. New chemicals that joined to tubulin do not be extrused by pgp. 5. Drugs joined to liposomes. 6. Interpheron to increase the efficacy of MoAbs in mdr reversion. 7. Photodynamic therapy. Other possibilities can be the use of MoAbs in diagnostic (immunodetection) by PET and SPECT: and the MoAbs joined to drugs and radioisotopes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Differential effects of paclitaxel and derivatives on guinea pig isolated heart and papillary muscle.

Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer types. Paclitaxel blocks cell division by stabilizing microtubules, a mechanism that also underlies its major side effects (neutropenia and neurotoxicity). Paclitaxel can also alter cardiac function, and to elucidate the mechanism of this activity, we tested the mechanical and electrical effects of paclitaxel and a series of analogs (docetaxel, taxol B, taxol C and N-methyltaxol C; 5-20 microM) on two different cardiac preparations, the isolated coronary perfused heart and the papillary muscle of the guinea pig. Paclitaxel and N-methyltaxol C induced conduction arrhythmias and reduced coronary flow and left ventricular systolic pressure in the isolated heart, whereas the other taxol derivatives tested had no significant effect. Moreover, paclitaxel blocked the vasodilator effect of bradykinin in the isolated heart. Paclitaxel and N-methyltaxol C produced a positive inotropic effect in papillary muscle, without alterations in the action potential. In the latter preparation, no significant variations were observed after treatment with the other taxol derivatives. The in vitro cardiodepressant and arrhythmogenic activity of paclitaxel is similar to that reported after its clinical administration and might be due to coronary vasoconstriction. The precise role of microtubules as modulators of intracellular calcium in cardiac and smooth muscle cells is at present unclear, because docetaxel and other taxol analogs, though they exhibited similar activity on tubulin, lacked cardiac effects.

Action Potentials↗
PubMed1996

Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules.

The phosphorylation state of tau changes during neurodevelopment and highly phosphorylated tau accumulates in the paired helical filaments found in Alzheimer's disease. In non-neuronal mammalian cells transiently expressed tau is predominantly not phosphorylated at sites known to be phosphorylated in paired helical filaments. However this pattern of phosphorylation is induced by both glycogen synthase kinase-3 alpha and -3 beta and here we show that this results in a change in the intracellular properties of tau. Within cells tau is bound to cytoskeletal structures and causes changes in cellular cytoarchitecture with the induction of thick and stable microtubule bundles. This morphology is lost when tau is co-expressed with glycogen synthase kinase-3 beta; microtubules become less stable and are not bound by tau. Independently of any direct or indirect effects on tau, glycogen synthase kinase-3 beta induces some but relatively slight changes in microtubule organization with the loss of a prominent centrosomal microtubular origin. The cytoskeleton is critical to cell function and within post-mitotic neurons has a highly specialized structure induced, in part, by the neuronal-specific microtubule-associated proteins such as tau. In vitro studies have suggested that the properties of tau are regulated by phosphorylation as highly phosphorylated tau does not promote tubulin polymer assembly. We have demonstrated, in intact cells, that tau highly phosphorylated in the presence of glycogen synthase kinase-3 beta loses the properties of microtubule binding and stabilization, suggesting that regulation of tau phosphorylation by this enzyme might be an important mechanism whereby cytoskeletal function is modulated during neurodevelopment and lost in neurodegeneration.

Animals↗
PubMed1997

The stathmin/tubulin interaction in vitro.

Stathmin is a highly conserved ubiquitous cytoplasmic protein, phosphorylated in response to extracellular signals and during the cell cycle. Stathmin has recently been shown to destabilize microtubules, but the molecular mechanisms of this function remained unclear. We show here that stathmin directly interacts with tubulin. We assessed the conditions of this interaction and determined some its quantitative parameters using plasmon resonance, gel filtration chromatography, and analytical ultracentrifugation. The stathmin/tubulin interaction leads to the formation of a 7.7 S complex with a 60-A Stokes radius, associating one stathmin with two tubulin heterodimer molecules as determined by direct quantification by Western blotting. This interaction is sensitive to pH and ionic environment. Its equilibrium dissociation constant, determined by plasmon resonance measurement of kinetic constants, has an optimum value of 0.5 microM at pH 6.5. The affinity was lowered with a fully "pseudophosphorylated" 4-Glu mutant form of stathmin, suggesting that it is modulated in vivo by stathmin phosphorylation. Finally, analysis of microtubule dynamics by video microscopy shows that, in our conditions, stathmin reduces the growth rate of microtubules with no effect on the catastrophe frequency. Overall, our results suggest that the stathmin destabilizing activity on microtubules is related to tubulin sequestration by stathmin.

Animals↗
PubMed2003

Amifostine has antiangiogenic properties in vitro by changing the redox status of human endothelial cells.

Amifostine is a broad-spectrum cytoprotective agent, selective for normal tissues. It is a pro-drug metabolised to the free thiol WR-1065 that may act as a scavenger of free radicals, generated in tissues exposed to chemotherapeutic agents or radiation. WR-1065 can be further oxidized to its symmetric disulfide WR-33278 or degraded to hydrogen peroxide (H2O2). Both WR-1065 and WR-33278 resemble endogenous polyamines. Although amifostine is used in some cases in the clinic, there are only few studies concerning its actions at the cellular level. We have previously shown that amifostine inhibits angiogenesis in vivo, affecting the expression of several angiogenic genes. In the present work, we studied the effect of amifostine on human umbilical vein endothelial cell (HUVEC) functions in vitro, in order to further clarify its mechanism(s) of action. Amifostine increased HUVEC proliferation, an effect that was reversed by the intracellular H2O2 scavenger sodium pyruvate, agents that increase intracellular cAMP levels and L-valine. On the other hand, amifostine decreased HUVEC migration, an effect that was reversed by L-valine or L-arginine but not sodium pyrouvate. The decrease in migration was in line with decreased tube formation on matrigel and decreased amounts of metalloproteinase-2 released into the culture medium of HUVEC. Finally, amifostine reduced tyrosine nitration of the cytoskeletal proteins actin and alpha-tubulin in a time dependent manner. This last action could be due to the reduced production of nitric oxide (NO) or to other not yet identified mechanisms. Collectively, our results suggest that amifostine acts on endothelial cells through pathways that affect the redox status of the cells, either by producing H2O2 or by modulating NO production.

Actins↗
PubMed2002

A mechanism for microtubule depolymerization by KinI kinesins.

Whereas most kinesins motor along microtubules, KinI kinesins are microtubule depolymerizing machines. Surprisingly, we found that a KinI fragment consisting of only the motor core is capable of ATP-dependent depolymerization. The motor binds along microtubules in all nucleotide states, but in the presence of AMPPNP, microtubule depolymerization also occurs. Structural characterization of the products of AMPPNP-induced destabilization revealed a snapshot of the disassembly machine in action as it precisely deformed a tubulin dimer. While conventional kinesins use the energy of ATP binding to execute a "powerstroke," KinIs use it to bend the underlying protofilament. Thus, the relatively small class-specific differences within the KinI motor core modulate a fundamentally conserved mode of interaction with microtubules to produce a unique depolymerizing activity.

Adenosine Triphosphate↗
PubMed1995

Stimulus-dependent alterations in macrophage microtubules: increased tubulin polymerization and detyrosination.

Murine macrophage microtubules are very dynamic. The majority of the microtubules (approximately 80%) exist in a rapidly depolymerizing pool (t1/2 approximately 30 seconds). The remaining 20% of the microtubules are in a more slowly depolymerizing pool (t1/2 approximately 7 minutes). Macrophage microtubules are responsive to cell stimulation with phorbol esters; upon cell stimulation there is a rapid increase in total microtubule polymer and number. In addition there is stimulus-induced detyrosination of alpha-tubulin in macrophage microtubules that is rapid and essentially complete, occurring in all microtubules rather than a subset of microtubules. Detyrosination of the macrophage microtubules in response to phorbol esters does not confer increased stability to these microtubules, since treated cells have nocodazole-induced depolymerization kinetics similar to that in non-stimulated macrophages. Regrowth of microtubules following washout of nocodazole is also rapid. Interestingly the regrown microtubules are initially in the tyrosinated form even in the presence of phorbol ester. These experiments provide in vivo support for the model that detyrosination of alpha-tubulin occurs in polymeric tubulin while retyrosination occurs in dimeric tubulin. Macrophage microtubules also demonstrate an unusually rapid response to extracellular stimuli and thus provide a unique model system in which to examine signal transduction events and modulation of microtubules.

Animals↗
PubMed1999

E-MAP-115 (ensconsin) associates dynamically with microtubules in vivo and is not a physiological modulator of microtubule dynamics.

Microtubule-associated proteins (MAPs) have been hypothesized to regulate microtubule dynamics and/or functions. To test hypotheses concerning E-MAP-115 (ensconsin) function, we prepared stable cell lines expressing conjugates in which the full-length MAP (Ensc) or its microtubule-binding domain (EMTB) was conjugated to one or more green fluorescent protein (GFP) molecules. Because both distribution and microtubule-binding properties of GFP-Ensc, GFP-EMTB, and 2x, 3x, or 4xGFP-EMTB chimeras all appeared to be identical to those of endogenous E-MAP-115 (ensconsin), we used the 2xGFP-EMTB molecule as a reporter for the behavior and microtubule-binding function of endogenous MAP. Dual wavelength time-lapse fluorescence imaging of 2xGFP-EMTB in cells microinjected with labeled tubulin revealed that this GFP-MAP chimera associated with the lattice of all microtubules immediately upon polymerization and dissociated concomitant with depolymerization, suggesting that dynamics of MAP:microtubule interactions were at least as rapid as tubulin:microtubule dynamics in the polymerization reaction. Presence of both GFP-EMTB chimeras and endogenous E-MAP-115 (ensconsin) along apparently all cellular microtubules at all cell cycle stages suggested that the MAP might function in modulating stability or dynamics of microtubules, a capability shown previously in transiently transfected cells. Although cells with extremely high expression levels of GFP-EMTB chimera exhibited stabilized microtubules, cells expressing four to ten times the physiological level of endogenous MAP exhibited microtubule dynamics indistinguishable from those of untransfected cells. This result shows that E-MAP-115 (ensconsin) is unlikely to function as a microtubule stabilizer in vivo. Instead, this MAP most likely serves to modulate microtubule functions or interactions with other cytoskeletal elements.

Female↗
PubMed1986

Specific postsynaptic density proteins bind tubulin and calmodulin-dependent protein kinase type II.

Cytoskeletal interactions which contribute to the assembly of the postsynaptic density (PSD) were investigated. PSDs bound 125I-tubulin specifically with an apparent Km of 2 X 10(-7) M and a Bmax of about 1 nmol/mg of protein. 125I-Tubulin blots revealed that a group of polypeptides between Mr 135,000 and 147,000 (P-140) was a major tubulin-binding PSD component. The P-140 polypeptides were highly enriched in the PSD fraction of purified synaptosomes and could not be detected in crude brain cytoplasm preparations. These polypeptides were subject to phosphorylation by endogenous calmodulin-dependent protein kinase type II, with a concomitant reduction in 125I-tubulin binding. The tubulin-binding polypeptides could also associate with the radiolabeled alpha- and beta-subunits of the calmodulin-dependent protein kinase. These observations are consistent with a role for the P-140 polypeptides in organizing the molecular structure of the PSD. The data also suggest that this structure may be modified by Ca2+-sensitive phosphorylation, thus permitting neuronal activity to modulate the cytoskeletal interactions of the PSD.

Animals↗
PubMed1992

Regulation of cytoplasmic tubulin carboxypeptidase activity during neural and muscle differentiation: characterization using a microtubule-based assay.

A cycle of posttranslational modification of alpha-tubulin has previously been described in higher eukaryotes, in which a C-terminal tyrosine residue is removed and replaced by two complementary cytoplasmic enzymes. The activity of the detyrosinating enzyme, tubulin carboxypeptidase (TCP), and its potential for regulating the level of detyrosinated (Glu) subunits in microtubules (MTs) is of great interest, since TCP catalyzes the primary modification of tubulin and since the level of Glu alpha-tubulin in MTs increases during a variety of differentiative and morphogenetic events. As a first step in examining the role of TCP in cellular morphogenesis, it was necessary to develop an assay for TCP with sufficient sensitivity and specificity to detect TCP activity during these events. Unlike previously described assays for TCP, ours makes use of the affinity TCP exhibits for MTs. NGF-induced neurite outgrowth in PC-12 cells was accompanied by a moderate (approximately 2-fold) increase in TCP activity, while myogenesis of L6 cells resulted in an almost insignificant decrease in activity. Measurements of TCP activity during differentiation were correlated with the level of extract Tyr tubulin, which increased (approximately 37%) during neurite outgrowth and was unchanged during myogenic differentiation. Our results suggest that TCP activity is regulated relative to its substrate, Tyr tubulin, and that changes in MT dynamics, rather than enzymatic activities, are the primary determinants of MT posttranslational modification state during differentiation. In addition, the assay we have devised for TCP and the characterization of TCP during differentiation may allow the future delineation of the mechanism(s) of regulation of TCP and the role this enzyme plays in modulating MT function during differentiation.

Adrenal Gland Neoplasms↗
PubMed1997

Modulation of protein kinases and microtubule-associated proteins and changes in ultrastructure in female rat pituitary cells: effects of estrogen and bromocriptine.

This study focused on the intracellular signal transduction system and microtubule-associated proteins (MAPs), such as MAP-2 and Tau protein. The modulation of these proteins and their correlation with ultrastructural changes were investigated in rat pituitary prolactin (PRL) cells. Adult female Wistar rats were treated with estrogen and bromocriptine and their pituitary glands were removed for analysis of the expression of tubulin, MAP-2, Tau protein, protein kinase C (PKC), and calcium calmodulin (CaM) kinase. Western blot analysis showed that estrogen increased and bromocriptine decreased the expression of PKC alpha, beta 1, beta 2, CaM kinase alpha, beta, MAP-2, and Tau protein. MAP-2 and Tau protein, which are cytosolic proteins, being translated on free ribosomes, were associated with the membrane of whirling rough endoplasmic reticulum (RER) in estrogen-treated cells and dissociated with vesiculated RER induced by bromocriptine. These results suggested that the modulation of MAP-2 and Tau protein may reflect changes of PKC and CaM kinase, and that the quantitative changes and intracellular modulation of MAPs induced by estrogen and bromocriptine, i.e., estrogen-induced association and bromocriptine-induced dissociation of MAP-2 and Tau protein with membrane of RER, may reflect the dynamics of microtubules and are associated with structural changes in the RER and changes in the synthesis and intracellular transport of PRL.

Animals↗
PubMed1988

Similar time course changes in striatal levels of glutamic acid decarboxylase and proenkephalin mRNA following dopaminergic deafferentation in the rat.

The time course changes in levels of mRNA encoding glutamic acid decarboxylase (GAD) and proenkephalin (PPE) was analyzed in the rat striatum following unilateral lesion of substantia nigra with 6-hydroxydopamine. The levels of both GAD and PPE mRNAs increased after the dopaminergic deafferentation, reaching concomitantly a maximal twofold increase on day 25. Thereafter, the mRNA levels declined; at 4 months, the amount of PPE mRNA remained slightly elevated whereas GAD mRNA had returned to the control value, suggesting the action of a compensatory mechanism. We also observed a rise of glial fibrillary acidic protein mRNA level which reflects a reactive astrocytosis. In contrast, alpha-tubulin mRNA level remained unchanged, indicating that no significant synaptogenesis occurs in this experimental situation. No obvious modification in mRNA levels was detected in the striatum contralateral to the lesion. These results highlight the role of the modulation of gene expression in adaptive processes to dopamine deficiency in striatal efferent pathways. Its relevance to the pathophysiology of Parkinson's disease is discussed.

Animals↗
PubMed1992

Nucleoside diphosphate kinase does not directly interact with tubulin nor microtubules.

Nucleoside diphosphate kinase has been shown to play a role in proliferation and development. Microtubules have been evoked as a possible target of NDP kinase action; in particular it was proposed that NDP kinase could regulate the cellular pool of polymerizable GTP-tubulin by direct phosphorylation of tubulin bound GDP. We show that this reaction does not occur in vitro and also that NDP kinase does not bind to microtubules both in the presence and absence of MAPs. Thus, any possible physiological effect of NDP kinase on microtubule dynamics is exerted only by modulating the concentrations of free guanine nucleotides in the vicinity of microtubules.

Animals↗
PubMed2004

Subcellular localization of multiple PREP2 isoforms is regulated by actin, tubulin, and nuclear export.

The PREP, MEIS, and PBX families are mammalian members of the TALE (three amino acid loop extension) class of homeodomain-containing transcription factors. These factors have been implicated in cooperative DNA binding with the HOX class of homeoproteins, but PREP and MEIS interact with PBX in apparently non-HOX-dependent cooperative DNA binding as well. PREP, MEIS, and PBX have all been reported to reside in the cytoplasm in one or more tissues of the developing vertebrate embryo. In the case of PBX, cytoplasmic localization is due to the modulation of nuclear localization signals, nuclear export sequences, and interaction with a cytoplasmic anchoring factor, non-muscle myosin heavy chain II B. Here we report that murine PREP2 exists in multiple isoforms distinguished by interaction with affinity-purified antibodies raised to N- and C-terminal epitopes and by nuclear versus cytoplasmic localization. Alternative splicing gives rise to some of these PREP2 isoforms, including a 25-kDa variant lacking the C-terminal half of the protein and homeodomain and having the potential to act as dominant-negative. We further show that cytoplasmic localization is due to the concerted action of nuclear export, as evidenced by sensitivity to leptomycin B, and cytoplasmic retention by the actin and microtubule cytoskeletons. Cytoplasmic PREP2 colocalizes with both the actin and microtubule cytoskeletons and coimmunoprecipitates with actin and tubulin. Importantly, disruption of either cytoskeletal system redirects cytoplasmic PREP2 to the nucleus. We suggest that transcriptional regulation by PREP2 is modulated through the subcellular distribution of multiple isoforms and by interaction with two distinct cytoskeletal systems.

Actins↗
PubMedDate not supplied

Two-dimensional polyacrylamide gel electrophoresis in experimental hepatocarcinogenesis studies.

High resolution two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) in combination with computer-assisted densitometry was used to analyze sequential changes in polypeptide expression during chemically (aflatoxin Bl; AFB), spontaneously, and oncogene (v-Ha-ras, v-raf, and v-raflv-myc)-induced experimental rat hepatocarcinogenesis. Two-dimensional mapping of [35S]methionine and [32P]orthophosphate-labeled whole cell lysate and nuclear polypeptides revealed subsets of polypeptides specific for each transformation modality in the in vitro rat liver epithelial (RLE) transformation model. Many of the observed changes in whole cell lysate preparations were localized to specific subcellular organelles. Significant alterations in the expression of the extracellular matrix protein, fibronectin, as well as tropomyosin- and intermediate filament-related polypeptides (vimentin, beta-tubulin, cytokeratins 8, 14, and 18, and actin) were observed among the various transformant cell lines. Whereas alterations in the tropomyosin isoforms appeared to be transformation specific, concomitant modulation of intermediate filament expression was related more to the differentiation state of the individual cell lines than to the transformed phenotype. To integrate protein and DNA information of polypeptides believed to be critically involved during cellular transformation, N-terminal amino acid microsequencing of selected nuclear polypeptides was performed. Preliminary results suggest that N-terminal blockage of rat liver epithelial nuclear proteins to be minor (approximately 20%) with sequencing sensitivity of one pmol. These studies extend our on-going efforts toward the establishment of computerized database of rat liver epithelial cellular proteins (Wirth et al., Electrophoresis, 1991, 12, 931-954) to aid in the delineation of polypeptides critically involved in cellular growth and differentiation as well as transformation.

Amino Acid Sequence↗
PubMed2005

G protein activation is prerequisite for functional coupling between Galpha/Gbetagamma and tubulin/microtubules.

Heterotrimeric G proteins participate in signal transduction by transferring signals from cell surface receptors to intracellular effector molecules. Interestingly, recent results suggest that G proteins also interact with microtubules and participate in cell division and differentiation. It has been shown earlier that both alpha and betagamma subunits of G proteins modulate microtubule assembly in vitro. Since G protein activation and subsequent dissociation of alpha and betagamma subunits are necessary for G proteins to participate in signaling processes, here we asked if similar activation is required for modulation of microtubule assembly by G proteins. We reconstituted Galphabetagamma heterotrimer from myristoylated-Galpha and prenylated-Gbetagamma, and found that the heterotrimer blocks Gi1alpha activation of tubulin GTPase and inhibits the ability of Gbeta1gamma2 to promote in vitro microtubule assembly. Results suggest that G protein activation is required for functional coupling between Galpha/Gbetagamma and tubulin/microtubules, and supports the notion that regulation of microtubules is an integral component of G protein mediated signaling.

Animals↗
PubMed1997

Microtubules suppress actomyosin-based cortical flow in Xenopus oocytes.

Several cell motility processes including cytokinesis and cell locomotion are dependent on the interplay of the microtubule and actomyosin cytoskeletons. However, because such processes are essentially visual phenomena, interactions between the two cytoskeletal systems have been difficult to study quantitatively. To overcome this difficulty, we have developed the Xenopus oocyte as an inducible, quantitative model system for actomyosin-based cortical flow and then exploited the strengths of this system to assess the relationship between microtubules and cortical flow. As in other systems, oocyte cortical flow entails: (1) redistribution of cortical filamentous actin (f-actin); (2) a requirement for actomyosin; (3) redistribution of cell surface proteins; (4) a requirement for cell surface protein mobility; and (5) directed movement of cortical organelles. Cortical flow rate in the oocyte system is inversely proportional to the level of polymeric tubulin and microinjection of free tubulin has no effect on the rate of cortical flow. Enhancement of microtubule polymerization inhibits cortical f-actin cable formation during cortical flow. The effects of microtubule depolymerization on cortical flow are rapid, independent of transcription or translation, independent of effects on the oocyte intermediate filament system, and independent of the upstream stimulus for cortical flow. The results show that the microtubules themselves, or a factor associated with them, suppress cortical flow, either by mechanically resisting flow, or by modulating the actomyosin cytoskeleton.

Actins↗
PubMed2005

Force production by disassembling microtubules.

Microtubules (MTs) are important components of the eukaryotic cytoskeleton: they contribute to cell shape and movement, as well as to the motions of organelles including mitotic chromosomes. MTs bind motor enzymes that drive many such movements, but MT dynamics can also contribute to organelle motility. Each MT polymer is a store of chemical energy that can be used to do mechanical work, but how this energy is converted to motility remains unknown. Here we show, by conjugating glass microbeads to tubulin polymers through strong inert linkages, such as biotin-avidin, that depolymerizing MTs exert a brief tug on the beads, as measured with laser tweezers. Analysis of these interactions with a molecular-mechanical model of MT structure and force production shows that a single depolymerizing MT can generate about ten times the force that is developed by a motor enzyme; thus, this mechanism might be the primary driving force for chromosome motion. Because even the simple coupler used here slows MT disassembly, physiological couplers may modulate MT dynamics in vivo.

Animals↗