Although molecular constituents of signal transduction tracts are quickly being identified, how elements of these tracts are positioned spatially and how signals traverse the intracellular environment from the cell surface to the karyon or to other cytoplasmatic marks are non good understood. The find of signaling molecules that interact with microtubules ( MTs ) , every bit good as the multiple effects on signaling tracts of drugs that destabilize or hyperstabilize MTs, indicate that MTs are likely to be critical to the spacial organisation of signal transduction. Microtubule forming Centres ( MTOCs ) , which include fungous spindle pole organic structures and central body in higher eucaryotes, are a structurally diverse group of cell organs that portion a conserved function in microtubule nucleation and spindle formation. However, recent surveies propose that the map of MTOC constituents extends far beyond these established functions. Numerous cell rhythm regulators, checkpoint proteins and microtubule plus tip binding proteins localize to MTOCs during the cell rhythm, proposing that these cell organs serve as cellular scaffolds. In add-on, several MTOC constituents such as ? -tubulin and its associating proteins have been straight implicated in the control of cell rhythm patterned advance, activation of checkpoint responses and the ordinance of microtubule organisation and kineticss.
Introduction Microtubules are indispensable cytoskeletal polymers that are made of reiterating ?/?-tubulin heterodimers and are present in all eucaryotes. Microtubules affect cell form, cell conveyance, cell motility, and cell division. All of these maps involve the interaction of microtubules with a big figure of microtubule-associated proteins ( MAPs ) , which are of import for the ordinance and distribution of microtubules in the cell. Of particular involvement are centrifugal proteins of the kinesin and dynein households, which use ATP hydrolysis to travel ladings along microtubules or microtubules with regard to each other. Each microtubule is formed by the parallel association of protofilaments, additive polymers of tubulin dimers that are bound caput to tail. The tubulin sequence and construction contain the information required for the self-assembly of protofilaments into polar, dynamic microtubules, which in bend interact with a assortment of cellular factors ( 20 ) . Microtubules are extremely dynamic and can exchange stochastically between turning and shriveling stages, both in vivo and in vitro. This nonequilibrium behaviour, known as dynamic instability ( 20 ) , is based on the binding and hydrolysis of GTP by tubulin fractional monetary units. Each tubulin monomer binds one molecule of GTP. The binding to ?-tubulin at the N site is nonexchangeable, whereas the binding to ?-tubulin at the E site is exchangeable. Lone dimers with GTP in their E site can polymerise, but, after polymerisation, this base is hydrolyzed and becomes nonexchangeable.
Although the complexness of microtubule regulative tracts is non understood decently, the usage of fluorescent derived functions
and word picture of taxol-resistant tubulin mutations, with our turning cognition of the construction of the tubulin-taxol composite, have improved much about molecular inside informations. Tubulin Dimer Structure The construction of the tubulin dimer at 3.7- & A ; Aring ; declaration ( Figure 1a ) has been obtained by negatron crystallography of zinc-induced tubulin sheets stabilized with taxol ( 20 ) .The N-terminal nucleotide-binding sphere ( residues 1-206 ) is formed by the alternation of parallel beta strands ( S1-S6 ) and spirals ( H1-H6 ) . The nucleotide-binding pocket is formed by each of the cringles linking each strand and spiral ( loops T1-T6 ) and the N-terminal terminal of the nucleus spiral ( H7 ) . After the nucleus spiral is a smaller, 2nd sphere that is formed by three spirals ( H8-H10 ) and a assorted beta sheet ( S7-S10 ) . The C-terminal part is formed by two antiparallel spirals ( H11 and H12 ) that cross over the old two spheres. In the dimer the base in the ?-subunit ( GTP ) is buried at the intradimer interface, readily explicating the nonexchangeability of the site ( Figure 2b ) . The base at the E site is partly exposed on the surface of the dimer, leting its exchange in solution. Figure 1 ( a ) Ribbon diagram of the negatron crystallography construction of the tubulin dimer. Nucleotides are shown in pink and taxol in yellow. MAPs Microtubule-associated proteins ( MAPs ) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs bind to the tubulin subunits that make up microtubules to modulate their stableness. A big assortment of MAPs have been identified in many different cell types, and they have been found to transport out a broad scope of maps. These include both stabilising and destabilizing microtubules, steering microtubules towards specific cellular locations, cross-linking microtubules and interceding the interactions of microtubules with other proteins in the cell. Some of them restricted to particular cell types. For illustration isoforms of MAP1 and MAP2 are expressed chiefly in nerve cells, and MAP7 is restricted to epithelial cells ( 14 ) .Aberrant look of MAPs and their relevancy to the immune phenotype of a broad scope of malignances to microtubule-targeting agents have been documented ( 14 ) . MTs interact with a figure of adhering proteins and ordinance can happen at many degrees. For more inside informations about this you can mention the article S. Honore. et Al ( 2005 ) . ( B ) Structural elements environing the N-site base at an intradimer interface. Loops T1-T6 correspond to ?-tubulin ; loop T7* corresponds to the ?-subunit within the dimer.
Is MAPs holding any function in cell rhythm? Gene ontology survey of MAPs from Drosophila embryos, shown that 9 % proteins affecting in cell cycle/mitosis ( 11 ) . Staying MAPs besides have assortment of maps. By utilizing RNAi surveies besides it ‘s demonstrated that many MAPs significantly affects the cell rhythm ( ) . Chiefly five cistrons ( CG7033, CG8231, CG8258, CG8351, and CG5525 ) showed monopolar spindles with decreased MT denseness in add-on to by and large low Numberss of MTs in interphase cells, in relation to wild-type cells.
Figure 2 Functional Classification of 270 Drosophila Embryonic MAPs
Microtubules and signal transduction In the past decennary, surveies of the cytoskeleton have fused, about by stealing, with surveies of signal transduction. It has become clear that the cell ‘s system of cytoskeletal fibrils and its web of signaling tracts are closely linked and map hand in glove to bring forth a cell phenotype tailored to the immediate conditions of the cell. In add-on, when cells are remodeled the cytoskeleton is likely both consequence and cause: it responds to signals ; it organizes signaling tracts in infinite ; and it may execute signaling maps itself. Because it comprises additive elements that span the cell, the cytoskeleton is well-constructed for incorporating information.
We will see one elegant illustration that how microtubule responds to the extracellular signal. Fibroblasts in cell civilization provide a comparatively simple system for analyzing how extracellular signals reorganise and polarise the microtubule cytoskeleton. Grown in the absence of serum, fibroblasts contain chiefly labile microtubules which grow and shrink quickly. But when serum is restored to the medium, the cells produce an array of stable microtubules ( 6 ) , which can be detected by their post-translational alterations and opposition to depolymerizing drugs. These microtubules extend from the microtubule forming centre ( MTOC ) near the karyon to the fringe of the cell, and are oriented specifically toward the taking border of cells at a lesion site in the cell monolayer. The MTOC itself besides moves to a place between the karyon and the taking border of the cells ( 1 ) . Mechanisms for microtubule signal transduction
MT sequestering and release, MT bringing and MT staging of signaling molecules ( figure 3 ) . The binding of CI-Costal 2 and
Figure 3. Three basic mechanisms for MT-mediated signal transduction are shown. The signaling factor, represented by a domain, ( a ) is shown to interact straight with the MT, ( B ) via a motor protein or ( hundred ) via a putative staging factor. ( a ) For sequestering and release, three possible release mechanisms are envisioned: ( I ) signal induced alteration ( represented by a ) of the factor itself, ( two ) of the MT or ( three ) , enhanced MT depolymerization. ( degree Celsius ) The scaffolding factor ( represented by a cylinder ) is shown to undergo a conformation alteration upon adhering to the MT and this generates a binding site for the signaling factor. Other mechanisms ( e.g. post-translational alteration ) may trip the binding of the staging and signaling factors. NF B-I B to the MT surface may be illustrations of the sequestering and release mechanism ( ) . Activation and release of MT bound signalling factors could be accomplished by: alteration of the factor, alteration of the MT and/or dislocation of the MT. The latter two release mechanism are specific are specific for MTs and there is grounds that MT kineticss might be regulated by signal transduction. Each of these mechanisms might besides work in the rearward way, to sequester repressive factors during signal transduction.
MT-mediated bringing could move either by presenting signaling factors to other constituents on the MT surface or to specific sites in the cell. MLK2-KIF3 may be an illustration of the former, and an unidentified motor in the Wnt signaling tract may be an illustration of the latter. Activation of this mechanism by signal transduction could happen through enhanced motor-cargo interaction, enhanced motor-MT interaction, or stimulation of the motor itself. Kinesin polypeptides are known to be phosphorylated and this may modulate their interaction with lading ( 12, 13 ) . Post-translational alteration of tubulin enhances kinesin adhering ( 5, 10 ) , and may lend to the specific interaction of kinesin with stabilised MTs.
Drugs that breakdown MTs ( e.g. colchicine, nocodazole, Velban ) and drugs that hyperstabilize MTs ( e.g. taxol and taxotere ) have specific effects on diverse cellular procedures affecting signal transduction, for illustration, cell proliferation, cistron look, receptor signaling, programmed cell death, and cell polarisation ( Table 1 ) ( 7 ) . These drugs by and large bind specifically to tubulin and hold comparatively few other direct cellular marks, connoting that MTs may be involved
Table 1. Effectss of agents that break down or stabilise microtubules on signal transduction regulated procedure
in at least some of the signaling pathways modulating these procedures. For illustration, MT depolymerizing agents stimulate proliferation, whereas MT stabilising agents inhibit proliferation, proposing some kind of MT-mediated sequestering and release mechanism. MTOC and ?- tubulin Microtubule forming centre ( MTOC ) is a general term depicting a category of specialised constructions that direct the assembly, orientation and organisation of microtubules in eucaryotic cells. The function of MTOC as a cardinal organiser of the microtubule cytoskeleton has been known for over a century, yet the mechanism by which MTOCs accomplished this function remained a enigma for some clip. In recent old ages, a wealth of information has emerged. This is mostly due to the find of ?- tubulin, a new member of the tubulin super-family ( 15 ) . Numerous surveies indicate that MTOCs and in peculiar, ?- tubulin containing composites, map in extra microtubule processes other than modulating microtubule assembly and construction. A figure of proteins involved in cell rhythm ordinance, checkpoints and microtubule organisation and map to place to MTOCs and look to be regulated at these sites in a mode that is of import for their map ( fig 4 ) . For illustration, mutants impacting the ?TuSc appear to hold effects on microtubule organisation and kineticss ( 4, 24, 25 ) . MTOCs and cell rhythm patterned advance
During the cell rhythm, the precise timing of cardinal cellular procedures such as spindle arrangement, mitosis and cytokinesis is indispensable for high fidelity chromosome segregation. Temporal organisation of these events is coordinated by a group of proteins jointly termed cell rhythm regulators. Figure 4 ? tubulin and MTOC constituents map in assorted cell rhythm processes In recent old ages, surveies in barm have revealed that many regulators localize to the spindle pole organic structures ( SPBs ) during the cell rhythm ( Fig. 4 ) . As a consequence, the engagement of SPB constituents in the coordination of cell rhythm events have been investigated and suggest extra functions for SPB constituents in spindle placement, mitotic issue and cytokinesis. Spindle positioning. SPBs may act upon the timing and executing of cellular procedures by moving as scaffolds that promote interactions between regulative proteins and their substrates at a critical topographic point and clip during the cell rhythm. One illustration of this coordination is pre-anaphase spindle arrangement in the budding barm ( Fig. 5 ) . The microtubule forming protein Kar9 is unsymmetrically recruited to the bud-bound SPB ( SPBb ) where it facilitates spindle alliance by steering stellar microtubules emanating from this pole into the bud ( 16-18 ) . During this clip, it is imperative that Kar9 remain asymmetric as the loss of Kar9 dissymmetry marks both SPBs towards the bud.
Figure 5. Emerging functions of SPB constituents. ( A ) Numerous cell rhythm regulators, checkpoint proteins and proteins involved in spindle arrangement localize to the SPBs. Some of these proteins such as Kar9 unsymmetrically place to merely one SPB while others such as Bim1 symmetrically localize to both SPBs.
( B ) SPBs are of import for proper spindle placement as they harbor many constituents of the Kar9 spindle positioning machinery. Intrinsic dissymmetries between the two SPBs may lend to the asymmetric localisation of Kar9 by suppressing Kar9 localisation at the SPBm and advancing its localisation to the SPBb. One possibility is that SPBs facilitate an interaction between Kar9 and the Cdc28/cyclin composite which regulates phosphorylation of Kar9 and its asymmetric localisation. Regulation and formation of Kar9 composites at SPBs is of import for proper interactions between microtubule plus terminals and the bud cerebral mantle. ( C ) Spindle arrangement is monitored by the spindle placement checkpoint ( SPC ) which consists of a figure of proteins that localize to SPBs. Events at the SPBm prolongs the localisation of the Bub2/Bfa1 at both SPBs which inhibits Tem1 from advancing mitotic issue. What restricts Kar9 to one SPB is ill understood, yet several lines of grounds suggest that SPBs may be the staging sites for the regulative machinery that governs Kar9 dissymmetry. One factor known to lend to the constitution of Kar9 dissymmetry is phosphorylation of Kar9, mediated by the cell rhythm regulative kinase Cdc28, its associated early B-type mitotic cyclins ( Clb3, Clb4 and Clb5 ) , and the microtubule tie ining protein Bik1 ( Fig. 5 ) ( 16-18 ) .
Several mechanisms have been proposed to explicate how Kar9 phosphorylation at the SPB translates into its asymmetric distribu-tion. One hypothesis is that phosphorylation of Kar9 at Ser197 and Ser496 by Cdc28/Clb4 occurs specifically at the mother-bound SPB ( SPBm ) , which decreases its affinity for Bim1 at this pole ; thereby advancing the comparative enrichment of Kar9 at the SPBb. Alternate surveies propose that phosphorylation of Kar9 occurs at the SPBb via Cdc28/Clb5 and Bik1, and enhances Kar9 ‘s specific accretion at the bud-bound pole and its association with microtubule +ends. Though the precise participants and effects of phosphorylation in these mechanisms differ, both proposed mechanisms highlight a common challenging subject ; that built-in dissymmetries of the SPBs may act upon the ability of Cdc28 and the cyclins to modulate Kar9 ( Fig. 5 ) . While the mechanism that drives dissymmetry of the SPB remains controversial, the consequences of these surveies are consistent with old findings that have identified built-in functional and biochemical mutual oppositions between the two SPBs with regard to their association with extra proteins, their nucleating capablenesss and their cellular heritage following cytokinesis.
Similarly, asymmetric distribution of cytoplasmatic dynein, which is required for keeping the place of the spindle
during anaphase, and for pre-anaphase spindle arrangement in the absence of Kar9, is besides a necessary demand for proper spindle orientation in barm. Control of dynein dissymmetry to the SPBb is of import for the arrangement of this pole into the bud during anaphase elongation and is partly dictated by the SPB constituent Cnm67 and Cdc28 in combination with the late Btype cyclins, Clb1 and Clb2. In add-on, the several functions of early and late B-type cyclins in Kar9 and dynein map ensures that both mechanisms for positioning the spindle are non active at the same clip. Therefore, the SPBs can be viewed as functioning a cardinal function in organizing early and late spindle arrangement by scaffolding Cdc28 with different cyclins.
Mitotic issue and cytokinesis. Proper arrangement of the spindle and the SPBb is required for the oncoming of anaphase and issue from mitosis in budding barm. In the budding barm, mitotic issue occurs via a protein signaling cascade called the Mitotic Exit Network ( MEN ) . The MEN tract triggers the release of the evolu-tionarily conserved phosphatase Cdc14 from the nucleole, which de-phosphorylates and regulates MEN constituents and other marks that regulate the metaphase-anaphase passage and cytokinesis ( 2, 9, 23 ) . Many MEN constituents place to one or both of the SPBs during mitotic issue, proposing that SPBs scaffold this regulative machinery ( Fig. 5 ) . Furthermore, the SPB localisation of these proteins was found to hold functional relevancy on mitotic issue. For illustration in budding barm, entry of the SPBb into the bud consequences in an accretion of the MEN constituents Tem1 and Cdc15 to the SPBb and loss of Bub2, all of which coincide with mitotic issue. Importantly, localisation of Tem1 and Cdc15 to the SPBb is facilitated by the SPB constituents Nud1 and Cnm67 ( 3, 8 ) .This demonstrates that for budding barm, the constitution of mitotic issue depends on a spacial and temporal coordination between SPB arrangement and localisation of the MEN machinery. In fission barm, a tract analogue to the MEN known as the Septation Initiation Network or SIN, likewise involves the local-ization of SIN constituents to SPBs, nevertheless the function of the SIN chiefly facilitates the proper timing of cytokinesis. During division, contraction of the cytokinetic actomyosin ring ( CAR ) mediates septation and is coordinated with spindle formation and chromo-some segregation ( 19 ) . SPBs scaffold the polo-like kinase Plo1 and the SIN constituent Cdc7, both of which are required for proper CAR formation and septation. Loss of this localisation consequences in a cell rhythm hold due to activation of the spindle assembly checkpoint. Additionally, SPBs besides scaffold the SIN constituent Cdc11 which is required for the subsequent localisation and activation of other downstream SIN constituents. Jointly, surveies in budding and fission barms identify the SPBs as evolutionarily conserved staging sites for proteins involved in spindle arrangement, mitotic issue and cytokinesis. The precise temporal and spacial localisation of these regulative tracts to SPBs suggests that as scaffolding sites, SPBs promote or keep local environments that facilitate the ability of these proteins to regulate cell rhythm patterned advance. Intriguingly, the engagement of SPBs in cell rhythm patterned advance may be more complicated than merely a scaffolding function.
Spindle positioning checkpoint ( SPC ) . In budding barm, SPBs have been implicated in the checkpoint that proctors spindle arrangement. This checkpoint, termed the spindle placement checkpoint ( SPC ) , utilizes the little G-protein Tem1 as a maestro switch for either delaying or advancing mitotic patterned advance. When spindle arrangement is perturbed, Tem1 is maintained in an inactive province, thereby
suppressing the MEN until proper spindle arrangement is achieved. Many surveies have shown Tem1 inactivation to be partially maintained through the GAP activity of the GTPase triping heterodimer Bub2/Bfa1 ( Fig. 5 ) .Recently, SPBs have besides been implicated in interceding Tem1 inactivation, as Tem1 suppression was dependent on the relentless localisation of Bub2/Bfa1 to the SPBm instead than on their GAP activity. SPBs are proposed to be regulative scaf-folding sites for events that mediate Tem1 activation. As of yet, the mechanism between Tem1 activation and the relentless localisation of Bub2/Bfa1 to the SPBm remains unknown. However, interactions between Bub2/Bfa1 and Nud1 may supply the nexus in under-standing the engagement of SPBs in this checkpoint. A function for SPBs in the SPC is farther demonstrated by their ability to scaffold the checkpoint kinase Kin4. In response to spindle placement defects, Kin4 inhibits the MEN by advancing the activity of Bub2/Bfa1 ( ) . This is accomplished by antagonizing the activity of the polo-like kinase Cdc5, which activates the MEN through repressive phosphorylation of Bfa1. In response to spindle misalignment, Kin4 and Bub2/Bfa1 composite are localized together at both poles and Kin4 is able to keep Bub2/Bfa1 ‘s activity. Localization of Kin4 to SPBs besides requires the SPB constituent Nud1, therefore straight implicating a SPB constituent as a scaffold for members in this peculiar checkpoint. Decision
New grounds suggests that MT-associated proteins may besides hold functions in signal transduction. MTs themselves respond to signal transduction and this may be an of import facet of the integrating and polarisation of signaling tracts. Many other cellular procedures are affected by drugs that interfere with MT kineticss and stableness and one of the hereafter challenges will be to place the molecular footing for these effects. The function of MTOC constituents throughout the life rhythm of the cell is an exciting and complex country of survey. The fond regard of both spindle and cytoplasmatic microtubules to these sites supports an ability of these cell organs to move as maestro controls for cell rhythm patterned advance, arousing a checkpoint response, and organizing microtubule organisation during these events. The localisation of cell rhythm regulators, checkpoint proteins and microtubule plus tip binding proteins suggests that MTOCs have a staging map whereby they spatially coordinate protein interactions which translate into downstream events at the cerebral mantle and/or microtubule terminal. More interesting is the possibility that MTOC constituents straight participate in a more active function in these procedures such as take parting in protein signaling Cascadess. Surveies are uncovering that constituents of ?- tubulin composites appear to be premier campaigners for interceding the function of MTOCs in these assorted cell rhythm events. Mentions
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