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MARIETTA BIOL 309 - Microtubules and actin filaments:

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123 Microtubules and actin filaments: dynamic targets for cancer chemotherapy Mary Ann Jordan* and Leslie Wilsont Microtubules and actin filaments play important roles in mitosis, cell signaling, and motility. Thus these cytoskeletal filaments are the targets of a growing number of anti-cancer drugs. In this review we summarize the current understanding of the mechanisms of these drugs in relation to microtubule and actin filament polymerization and dynamics. In addition, we outline how, by targeting microtubules, drugs inhibit cell proliferation by blocking mitosis at the mitotic checkpoint and inducing apoptosis. The I~-tubulin isotype specificities of new anticancer drugs and the antitumor potential of agents that act on the actin cytoskeleton are also discussed. Addresses Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106-9610, USA *e-maih [email protected] re-mail: [email protected] Current Opinion in Cell Biology 1998, 10:193-130 http:llbiomednet.com/elecref/095506 7401000193 © Current Biology Ltd ISSN 0955-0674 Abbreviations MAD2 mitotic-arrest-deficient protein 2 OP18 oncoprotein 18 Introduction Microtubules and actin filaments are cytoskeletal protein polymers critical for cell growth and division, motility, signaling, and the development and maintenance of cell shape (reviewed in [1]). Polymerization of actin monomers into actin filaments and of ~tl~-tubulin dimers into microtubules occur by similar nucleation-elongation pathways, in which formation of a short polymer 'nucleus' is followed by elongation of the polymer at each end by the reversible, noncovalent addition of subunits. Neither microtubules nor actin filaments are simple equilibrium polymers; instead both exhibit complex polymerization dynamics that use energy provided by the hydrolysis of nucleotide triphosphates. The non-equilibrium dynamics of these reactions are crucial to the cellular functions of the two cytoskeletal proteins. Microtubule and actin filament polymerization dynamics The polar nature of the microtubule polymer and the hydrolysis of GTP that occurs during microtubule poly- merisation creates two unusual forms of dynamic behavior in cells and in vitro. One such form is dynamic instability [2], in which microtubule ends stochastically switch between episodes of prolonged growing and shortening. One microtubule end, the plus end, shows more dynamic instability behavior than the opposite or minus end. The other form of dynamic behavior, treadmilling, which is due to differences in the critical subunit concentrations at opposite microtubule ends [3,4], consists of net growing at microtubule plus ends and net shortening at minus ends. Treadmilling was shown, many years ago, to occur in vitro with microtubule populations rich in microtubule-associ- ated proteins, but the rate of treadmilling was thought by some investigators to be intrinsically too slow to be of use in microtubule-mediated cell processes. However, rapid treadmilling of microtubules has recently been demonstrated in living cells [5"] and the notion that treadmilling is an important form of dynamic behavior in cells has been rekindled [6"]. Figure 1 t0 t~ t2 t3 t4 t5 te Minus end Plus end , M~rotubule i i i $3~3;;;~;;;;;~ ..... ~3~ "_ ~ 2 2CCC 2 2~2 2 2 ..... ~CC _ ~ 2 _ _ ~ ........... i i Current Opinion in Cell Biolo~/' Simultaneous dynamic instability and treadmilling in a single microtubule. The diagram shows consecutive 'snapshots' of a microtubule exhibiting episodes of growing and shortening at both plus and minus ends, with net growth at the plus end and net shortening at the minus end. The plus end shows more dynamic instability behavior than the minus end. The shaded subunits represent a marked segment of tubulin subunits, which is treadmilling or flowing from the plus to the minus end (t o through t 6 are arbitrary time points). Microtubule dynamics are important for many microtubule- dependent processes in cells, the most dramatic of which is mitosis. When cells enter mitosis, the cytoskeletal microtubule network is dismantled and a bipolar, spindle- shaped array of microtubules is built that attaches to chromosomes and moves them to the two spindle poles. Microtubule dynamics are relatively slow in interphase cells, but increase 20- to 100-fold at mitosis. Both extensive dynamic instability and treadmilling (or flux) occur in mitotic spindles and the rapid dynamics of spindle124 Cytoskeleton microtubules play critical roles in the intricate movements of the chromosomes. The hydrolysis of ATP during polymerization of actin filaments also creates non-equilibrium dynamics. Actin filament treadmilling occurs both in vitro and in cells, with actin addition occurring at the 'barbed' ends of the filaments and actin loss occurring at the 'pointed' ends [1,7,8]. In principle, actin filaments could undergo dynamic instability; however, such behavior has not been observed. While microtubules have long been valuable targets for cancer chemotherapy, recent evidence (discussed below) indicates that the dynamics of microtubules, not just their presence, are critical for cell proliferation [9-11]. The same may be true for actin filaments [12"']. Kinetic suppression (stabilization) of microtubule dynamics is a common and powerful mechanism of antimitotic agents A large number of chemically diverse compounds, many of which are derived from natural products, bind to tubulin or microtubules and inhibit cell proliferation at the metaphase/anaphase transition of mitosis (see below) by acting on the mitotic spindle. Most such agents, including the vinca alkaloids and colchicine, inhibit microtubule polymerization at relatively high concentrations in vitro and in cells and thus have been thought to act solely by destroying the mitotic spindle (reviewed in [I1]). More recently, a new class of anti-tumor drug, which includes taxol, taxotere, discodermolide and the epothilones, was also found to inhibit cell replication by acting on microtubules [13,14,15"-17"]. The


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