As a major component of the cytoskeleton, microtubules consist of αβ-tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 Å cryst...

Data generated in the new National Cancer Institute drug evaluation program, which are based on inhibition of cell growth in 60 human tumor cell lines, were probed with nine known antimitotic agents using the COMPARE algorithm. Cytotoxicity data were available on approximately 7000 compounds at the time of the analysis, and, based on the criteria used, 82 compounds were selected as positive by ...

Interactions of tubulin with a number of guanine nucleotides modified at the 2' and 3' ribose hydroxyls were examined. Deoxy analogs of GTP were equal or superior to GTP in supporting tubulin polymerization, but analogs bearing either methyl or phosphate groups on the hydroxyls had significantly reduced ability to support polymerization. These substituted GTP analogs were hydrolyzed at the 5'-g...

A sensitive and reproducible method to measure relative levels of polymerized and soluble tubulin in cells has been developed. This method involves metabolically labeling cells with radioactive amino acids followed by lysis in a microtubule-stabilizing buffer, centrifugation to separate soluble from polymerized tubulin, resolution of the proteins in each fraction by two-dimensional gel electrop...

Acetaldehyde is known to form covalent adducts with tubulin and to inhibit microtubule formation. Available evidence indicates that lysine residues are prominently involved in adduct formation. Previous work has shown that lysines on tubulin can be divided into two general classes based upon their reactivity toward acetaldehyde; those of normal reactivity ("bulk" lysines) and a highly reactive ...

The effect of bovine brain calmodulin on the assembly of pure bovine brain tubulin has been examined in the presence and absence of microtubule-associated proteins (MAPs). In the absence of MAPs, calmodulin enhances the rate and extent of polymerization of pure tubulin, probably by sequestering Ca2+ from tubulin since the effect is mimicked by ethylene glycol bis(beta-aminoethyl ether)N,N,N',N'...

The microtubule-targeting agents (MTAs) are a very successful class of cancer drugs with therapeutic benefits in both hematopoietic and solid tumors. However, resistance to these drugs is a significant problem. Current MTAs bind to microtubules, and/or to their constituent tubulin heterodimers, and affect microtubule polymerization and dynamics. The PPARgamma inhibitor T0070907 can reduce tubul...

XMAP215 family members are potent microtubule (MT) polymerases, with mutants displaying reduced MT growth rates and aberrant spindle morphologies. XMAP215 proteins contain arrayed tumor overexpressed gene (TOG) domains that bind tubulin. Whether these TOG domains are architecturally equivalent is unknown. Here we present crystal structures of TOG4 from Drosophila Msps and human ch-TOG. These TO...

The mode of action of rhizoxin (1a), a new antitumor macrolide, was investigated. Rhizoxin inhibited fusion of the male and the female pronuclei in fertilized sea urchin eggs and inhibited cilia formation in the deciliated sea urchin embryos. In vitro, polymerization of tubulin isolated from porcine brains was completely inhibited at a 1 X 10(-5) M concentration of rhizoxin, and tubulin which h...

background: microtubules (mt) are important components of cell cytoskeleton and play key roles in cell motility mitosis and meiosis. they are also the targets of several anticancer agents which indicating their importance in maintaining cell viability. microtubular reorganization contributing to apoptotic morphology occurs in normal and neoplastic cells undergoing apoptosis induced by cytotoxic...