Microtubules

Microtubules are highly dynamic cytoskeletal polymers that reside in all eukaryotes and are essential for a wide variety of processes, including intracellular signal transduction, vesicular and organelle transport, development and maintenance of cell shape and cell locomotion, and regulation of cell division. The individual microtubule is formed by a linear association of protofilaments, which are composed of tubulin heterodimers a and b assembled in "head to tail" structure. Thus, each microtubule itself has a polarity, and the two ends have structural and kinetic differences. The "plus end" is characterized by a much more extensive duration of growing and shortening than the opposite "minus end"; thus the processes of polymerization and depolymer-ization of microtubules occur preferentially at the plus end. Microtubules form a lattice network of rigid hollow rods and undergo continual assembly and disassembly by the reversible addition and loss of tubulin dimers at the ends of microtubules. The linkage between the microtubule network and the contractile cytoskeleton has not been fully explored. However, an active crosstalk between microtubules and actin is required to control microtubule dynamics. This interplay has a key role in determining the cell polarity and regulation of migration. The microtubule-actin interaction is essential in regulation of endothelial integrity and wound repair [3-5]. The microtubule cytoskeleton is emerging as an important modulator of TNF-a-induced pulmonary endothelial permeability (Figure 1). A role for microtubule dynamics in permeability has been also demonstrated for other agents known to cause endothelial barrier damage such as nocodazole and hydrogen peroxide. The mechanisms by which TNF-a induces changes in the microtubule cytoskeleton are only beginning to be elucidated. TNF-a treatment induces microtubule destabilization and a decrease in the acetylated tubulin [6]. Microtubule stabilization by taxol or epothilone B inhibits actin rearrangement, vascular endothelial (VE)-cadherin redistribution, and

Figure 1 The effects of microtubule stabilization and p38 MAPK inhibition on TNF-a-induced endothelial permeability. (A, C) Representative tracings of normalized electrical resistance measured across endothelial cell monolayers (TER). Endothelial cells were exposed to vehicle (control) and TNF-a [20ng/ml], where the gray arrow on the abscissa indicates the time of challenge. TNF-a induced TER reduction was evident at 4 hours with a maximal effect at 10 hours of exposure. (A) Microtubule stabilization by paclitaxel (black arrow) significantly inhibits TNF-a-induced decreases in resistance. (C) P38 MAPK inhibition by SB203580 inhibits TNF-a induced permeability. (B) Bar graph demonstrating the effect of the microtubule-stabilizing agents paclitaxel end epothilone B on the maximal TNF-a-induced decrease in TER. No significant difference was noted between the two agents (p = 0.44). (see color insert)

Figure 1 The effects of microtubule stabilization and p38 MAPK inhibition on TNF-a-induced endothelial permeability. (A, C) Representative tracings of normalized electrical resistance measured across endothelial cell monolayers (TER). Endothelial cells were exposed to vehicle (control) and TNF-a [20ng/ml], where the gray arrow on the abscissa indicates the time of challenge. TNF-a induced TER reduction was evident at 4 hours with a maximal effect at 10 hours of exposure. (A) Microtubule stabilization by paclitaxel (black arrow) significantly inhibits TNF-a-induced decreases in resistance. (C) P38 MAPK inhibition by SB203580 inhibits TNF-a induced permeability. (B) Bar graph demonstrating the effect of the microtubule-stabilizing agents paclitaxel end epothilone B on the maximal TNF-a-induced decrease in TER. No significant difference was noted between the two agents (p = 0.44). (see color insert)

intercellular gap formation in response to TNF-a [6], suggesting first important crosstalk among the microtubule cytoskeleton, the actin microfilaments, and the zonula adherens proteins and second, that microtubules are opposing cellular contraction. This effect has been confirmed by the finding that microtubule disassembly leads to instant Rho kinase activation and cell contraction, potentially triggered by the release of Rho activating factors bound to microtubules ([7] and unpublished data).

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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