: Flavonoid-induced microtubule stabilization

International audienceFlavonoids are common components of the human diet and appear to be of interest in cancer prevention or therapy, but their structure-activity relationships (SAR) remain poorly defined. In this study, were compared 24 flavonoids for their cytotoxicity on cancer cells (B16 and Lewis lung) and their morphological effect on endothelial cells (EC) that could predict antiangiogenic activity. Ten flavonoids presented inhibitory concentrations for 50% of cancer cells (IC50, 48 h) below 50 microM: rhamnetin, 3',4'-dihydroxyflavone, luteolin, 3-hydroxyflavone, acacetin, apigenin, quercetin, baicalein, fisetin, and galangin. Important SAR for cytotoxicity included the C2-C3 double bond and 3',4'-dihydroxylation. Concerning the morphological effects on EC, only fisetin, quercetin, kaempferol, apigenin, and morin could induce the formation of cell extensions and filopodias at noncytotoxic concentrations. The SAR for morphologic activity differed from cytotoxicity and involved hydroxylation at C-7 and C-4'. Fisetin, the most active agent, presented cell morphology that was distinct compared to colchicine, combretastatin A-4, docetaxel, and cytochalasin D. Resistance to cold depolymerization and a 2.4-fold increase in acetylated alpha-tubulin demonstrated that fisetin was a microtubule stabilizer. In conclusion, this study disclosed several SAR that could guide the choice or the rational synthesis of improved flavonoids for cancer prevention or therapy

The immunophilin FKBP52 specifically binds to tubulin and prevents microtubule formation.: FKBP52 and Tubulin Functional interaction.

The FK506 binding protein FKBP52 belongs to the large family of immunophilins and is known as a steroid receptor-associated protein. Previous data suggest that FKBP52 is associated with the motor protein dynein and with the cytoskeleton during mitosis. Here we demonstrate a specific and direct interaction between FKBP52 and tubulin. The region of FKBP52 located between aa 267 and 400, which includes the tetratricopeptide repeat domain, is required for tubulin binding. We provide evidence that FKBP52 prevents tubulin polymerization and that an 84 residue sequence located in the C-terminal part of the molecule (aa 375-458) is necessary and sufficient for its microtubule depolymerization activity. In colocalization experiments in PC12 cells, FKBP52 is associated with tubulin in motile cellular compartments. Furthermore, we suggest that, by using siRNA, a decrease of FKBP52 expression in PC12 cells may lead to differentiated cell phenotype characterized by neurite extensions. Collectively, our data define an unexpected property of FKBP52 as a novel regulator of microtubule dynamics. The possible role of microtubule formation and tubulin binding of other immunophilins such as FKBP12 and FKBP51 is discussed

Association of p34cdc2 kinase and MAP kinase with microtubules during the meiotic maturation of Xenopus oocytes.

International audiencep34cdc2 protein is found in prophase, metaphase and activated Xenopus oocytes at a similar level whereas its kinase activity oscillates within meiosis. Using an anti-PSTAIRE antibody that recognizes Xenopus p34cdc2, it was demonstrated that the major part of p34cdc2 was associated with microtubules isolated in vitro from Xenopus oocytes. Conversely, tubulin was recovered in association with p34cdc2 in p13-Sepharose pellets. The abundance of the fraction of p34cdc2 which was associated with microtubules did not oscillate during the meiotic maturation and the activation process. By contrast, the histone H1 kinase activity of p34cdc2 estimated in microtubular oocyte pellets was much higher in metaphase than in prophase oocytes. Cyclin B, which is associated in vivo with p34cdc2 in prophase and metaphase oocytes, was also present in the microtubular fractions. However, cyclin was not necessary for the binding of p34cdc2 to microtubules since p34cdc2 from activated eggs, where cyclin was missing, still copurified with microtubules. Purified MAP2, but not tubulin, was able to bind to p34cdc2, demonstrating that the association between p34cdc2 and microtubules was mediated by microtubule-associated proteins. During the meiotic maturation of Xenopus oocytes, several protein kinases were activated, among them MAP kinase. MAP kinase also associated with microtubules. It was demonstrated that both p34cdc2 kinase and MAP kinase purified from Xenopus oocytes were able to phosphorylate in vitro rat brain MAP2. However both protein kinases phosphorylated different domains of MAP2, suggesting that they might regulate microtubules in different ways

A biochemical model for neurite outgrowth during brain development

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Microtuble-associated parameters as predictive markers of docetaxel activity in advanced breast cancer patients: Results of a pilot study

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