Thesis (M.S.)--Baylor University, 2006. / Includes bibliographical references (p. 63-65).

Thesis (M.S.)--Baylor University, 2006. / Includes bibliographical references (p. 105-109).

Thesis (M.S. in Biology) -- University of Dayton. / Non-Latin script record. Title from PDF t.p. (viewed 10/06/09). Advisor: Mark Nielsen. Includes bibliographical references (p. 41-43).

published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

The long-term goal of the Laboratory of Biology of Cytoskeleton is to explain in molecular terms the role of microtubules in cellular processes and to characterize proteins associated with microtubules and its organizing centers (MTOCs). The main attention of our research is focused on -tubulin and its role in microtubule nucleation. We have shown previously that besides its localization on centrosomes, -tubulin is found on celullar membranes (Macůrek et al., 2008), plant kinetochores (Dryková et al., 2003) and marginal bend of embryonal chicken erytrocytes (Linhartová et al., 2002). g-Tubulin also interacts with protein tyrosine kinases, that can regulate microtubule nucleation (Sulimenko et al., 2006; Macůrek et al. 2008). There are growing evidence that centrosomal proteins can affect genetic stability of the cell. g-Tubulin is involved in the regulation of the cell cycle (Vardy et al., 2002) and can participate in activation of checkpoint mechanism controlling the integrity of DNA. Recently, it has been proved its interaction with nuclear protein ATR (Zhang et al., 2007) and Rad51 (Lesca et al., 2005). That's why g-tubulin has been connected with the process of cancerogenesis. Cancer cells also display the changes in expression of b-tubulin isotypes (Katsetos et al., 2003). Moreover, increased level of...

Aurones belong to an uncommon class of plant flavonoids that provide the bright yellow coloration of some ornamental flowers and that possess a range of biological activities. Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the biologically active analogs developed in the course of this dissertation work were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5r). These two aurones 5a and 5r inhibited in vitro PC-3 prostate cancer cell proliferation with IC50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a for 18 days had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on a National Cancer Institute COMPARE analysis, studies using computer-based molecular docking and liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5r strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model. In summary, aurones possess a pharmacophore of considerable potential in the search for new antineoplastic agents for the clinical treatment of human cancers.

Thesis submitted to the Division of Veterinary and Biomedical Sciences. Bibliography: leaves 237-283.

Thesis (Ph.D.)--Baylor University, 2005. / Includes bibliographical references (p. 259-273).

The $ beta$-tubulin gene family of the parasitic nematode, Brugia pahangi consists of three to five $ beta$-tubulin sequences. Two genomic clones containing $ beta$-tubulin sequences were isolated and characterized. The $ beta$1-tubulin gene spans 3.8 kb, is organized into 9 exons and expresses an mRNA of 1.7 kb which codes for a protein of 448 amino acids. A partial nucleotide sequence of the second clone confirmed the isolation of a distinct $ beta$-tubulin sequence, $ beta$2-tubulin. The $ beta$1-tubulin transcript is found in microfilariae and adult worms, whereas the $ beta$2-tubulin transcript is predominant in male adult worms but absent from microfilariae. Results of this study also indicate that the maturation of the $ beta$1-tubulin message involves the acquisition of the conserved nematode 22-nucleotide splice leader sequence. Antipeptide IgGs raised against the divergent carboxy-terminal region of $ beta$1-tubulin recognize the same $ beta$-tubulin isoform pattern as a phylum cross-reactive monoclonal antibody. This result suggests that the $ beta$1-tubulin is highly represented in B. pahangi adults and microfilariae.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Also available online.