Cytoskeleton, microtubule activity

During blood clotting, complicated rearrangements of the cytoskeleton in activated platelets dramatically change the cell shape and promote clot formation (Figure 19-14). The cyftoskeleton of an unactlvated platelet consists of a rim of microtubules (the marginal band), a membrane skeleton, and a cytosolic actin network. The membrane skeleton in... 

FIG. 1. Timing and morphology of mouse embryos during the first two cleavages. The cortical activity of the one-cell embryo begins during late G2 phase shortly before the entry into the mitotic M phase. Scheme represents shapes of embryos and morphology of their chromatin and microtubule cytoskeleton. 

Two of the cytoskeletal components, the actin filaments and the microtubules have been studied with molecular rotors. The main component of the actin filaments is the actin protein, a 44 kD molecule found in two forms within the cell the monomeric globulin form (G-actin) and the filament form (F-actin). Actin binds with ATP to form the microfilaments that are responsible for cell shape and motility. The rate of polymerization from the monomeric form plays a vital role in cell movement and signaling. Actin filaments form the cortical mesh that is the basis of the cytoskeleton. The cytoskeleton has an active relationship with the plasma membrane. Functional proteins found in both structures... 

The cytoskeleton appears to have a significant role in the localization of different organelles, as well as in the active transport of vesicles (see Chs 8 and 28). Both microtubules (MTs) and actin filaments appear to be involved in these processes. For example, through its association with the minus end of MTs, the Golgi apparatus is... 

The activation of platelets and the action of polymorphonuclear leukocytes depend on changes in the microtubule cytoskeleton... 

Vinca dimer indole alkaloids (e.g. vinbiastine) act as spindle poisons. They bind tubulin, inhibiting polymerisation into microtubules, the major elements of the cytoskeleton [100]. Vinblastine itself and its analogue vinoreibine (Navelbine ) [101] are marketed for cancer therapies (Fig. 36). Vinflunine (Javlor ) is a member of second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinoreibine in several cancers (Fig. 36). It is now in phase III clinical... 

Vinflumine (Javlor ) is a second-generation Vinca alkaloid. It is more active than the nonfluorinated parent compound (vinorelbine) in several cancers (Figure 8.7). Vinflumine is currently in Phase III clinical trials as a chemotherapeutic agent against a variety of cancers (metastasic breast cancer, small cell lung cancer, and bladder cancer). This drug inhibits mitotic assembly, via inhibition of tubulin polymerization in microtubules, a major element of the cytoskeleton. Effects of fluorine substimtion on tubulin affinity or on metabolism are not responsible for the increased efficiency and decreased toxicity. The synthesis of vinflumine is reported in Chapter 4. ... 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

One of the major features in the sequence of cell division is the formation of the mitotic spindle and the subsequent separation of chromosomes into their respective daughter cells. An important element of the spindle is the highly conserved, helical molecule tubulin. In addition to spindle formation and the segregation of chromosomes in cell division, alternating helices of a- and -tubulin form the microtubules that form part of the cytoskeleton and have active roles in cell organelle organisation. 

What is the function of the membrane skeleton There is a group of hereditary diseases including spherocytosis in which erythrocytes do not maintain their biconcave disc shape but become spherical or have other abnormal shapes and are extremely fragile.269 272 Causes of spherocytosis include defective formation of spectrin tetramers and defective association of spectrin with ankyrin or the band 4.1 protein.265 273 Thus, the principal functions of these proteins in erythrocytes may be to strengthen the membrane and to preserve the characteristic shape of erythrocytes during their 120-day lifetime in the bloodstream. In other cells the spectrins are able to interact with microtubules, which are absent from erythrocytes, and to microtubule-associated proteins of the cytoskeleton (Chapter 7, Section F).270 In nerve terminals a protein similar to erythrocyte protein 4.1 may be involved in transmitter release.274 The cytoskeleton is also actively involved in transmembrane signaling. 

Cytoskeleton. Many cellular activities, such as motility, endocytosis, exocytosis, and cell division, rely on microfilaments and microtubules. A number of alkaloids have been detected which can interfere with the assembly or disassembly of microtubules (Table IV), namely, vincristine, vinblastine, colchicine, maytansine, maytansinine, and taxol. 

Cytoskeleton is defined as the sum of the various filamentous proteins of eukaryotic cells that remain after the cells are extracted with a mild detergent. The cytoskeleton includes actin filaments, two-stranded helical polymers, which form the microfilaments and the actin-binding proteins. Other components are microtubules and intermediate filaments. The cytoskeleton has not only a role in maintaining the shape of cells, it is also actively engaged in cell division, in the organisation and the dynamic movement of ceD organelles and in the movement of cells in chemotaxis. 

Many compounds that perturb the cellular cytoskeleton affect phagocytosis and macropinocytosis. Binding to actin filaments by the natural product cytochalasin D blocks both of these uptake mechanisms. Disruption of microtubules by the antimitotic agents colchicine and nocodazole inhibits macropinocytosis and affects some mechanisms of phagocytosis. The diuretic drug amiloride, which is an inhibitor of Na+/H+ antiporters, selectively blocks macropinocytosis. By activating protein kinase C, phorbol esters represent a class of small molecules that promote macropinocytosis. 

Neuromuscular transmission is initiated when an action potential travelling down the axon of a motor neurone arrives at the nerve terminal. Vesicles containing the neuromuscular transmitter, acetylcholine, are present in rows which line up either side of an "active zone". Active zones are transmitter release sites. The vesicles arrive at the active zones guided by the cytoskeletal matrix which is made up of microtubules, the contractile protein actin and the smooth endoplasmic reticulum. Attachment to the cytoskeleton is mediated by various proteins including s mapsin... 

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