Browsing by Subject "Cell migration"
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Item Extracellular matrix mechanics regulate cell signaling and migratory potential in cancer(2012-05) Srivastava, Jaya, active 2012; Ellington, Andrew D.; Zaman, Muhammad H. (Muhammad Hamid)The objective of the presented research is to examine the relationship between the cellular microenvironment and biochemical response of metastatic cells. Clinically recognized as a trait of cancer progression, the cellular microenvironment can have variable and distinct mechanical properties that are processed via cellular mechanosensing, resulting in a cellular biochemical response. A range of studies investigating the interactions between the cellular micromechanical environment and the cell's molecular response during disease progression have been made, yet remain absent of quantitative characterization of many of these coordinated responses. The fundamental inquiry that drives the following research attempts to elucidate how a cell perceives the physical microenvironment and converts that signal to a biochemical response. With the goal of providing insight to such responses, the presented research seeks to elucidate the following questions: (1) What are the integrated effects of ECM stiffness, ECM architecture, and breast cancer cell metastatic potential on cell migration? (2) How does endogenous tissue transglutaminase (tTG) cross-linking of the ECM scaffold effect ECM mechanical properties? (3) How does the architecture and stiffness of the extracellular matrix (ECM) effect the systems-level cellular migration and signaling response? (4) What are the integrated effects of ECM architecture and the targeted knockdown of integrin [beta]1 and MT1-MMP on cellular metastatic potential? The presented research utilizes an interdisciplinary approach, integrating experimental mechanics, biochemical analysis, cellular biology techniques, covalent chemistry, and various microscopy techniques, to investigate these events. In short, cancerous cells are cultured atop or within synthetic collagen type I ECMs of varying mechanical stiffness and structure. These cells are subsequently analyzed by molecular analysis and immunoassays, including quantitative PCR, Western blotting, and gelatin zymography, to acquire measures of the cellular response to perturbations of micromechanical environment. Time-lapse microscopy experiments and subsequent image analyses enable observations of cellular migratory potential through synthetic ECMs. Results indicate that cooperative synergy between ECM properties, cell-matrix adhesion, and pericellular proteolysis drive cell migratory potential of highly invasive tumorigenic cell populations. Collectively, these findings contribute to the cancer biology and mechanobiology fields by systematically extending current insights of matrix mechanics, cellular signaling, and cellular migratory potential in cancer.Item Novel roles of the proteins Oskar and Bluestreak in germ cell formation and migration(2007) Jones, Jennifer Rebecca, 1978-; Macdonald, Paul M.The formation of germ cells in Drosophila melanogaster is dependent on the presence of ribonucleoprotein complexes called polar granules. A key component of these complexes is Oskar, a novel protein which has been shown to nucleate the granules. To investigate whether Oskar plays a further role in polar granule formation, I cloned the oskar gene from D. immigrans flies (osk[superscript imm]) and introduced it into D. melanogaster flies using P-element transformation. I found that osk[superscript imm] was able to rescue both the posterior patterning and germ cell formation defects of embryos from oskar mutant mothers. In addition, I found that the polar granules of embryos containing only Osk[superscript imm] as a source of Oskar protein resemble those found in D. immigrans embryos, indicating a new role for Oskar in determining the morphology of the polar granules. Germ cell formation in Drosophila is succeeded by migration of the germ cells to the site of gonad formation. A second line of research presented in this dissertation describes analysis of a novel protein important for both germ cell formation and migration, Bluestreak (Blue). Embryos from either heterozygous or homozygous Blue-mothers display defects in germ cell number and shape. I found that the ovaries of Blue-females have defects in the localization of Staufen and Oskar, sufficient to cause a reduction in pole cell number in embryos. In addition, genetic analysis of the interaction between Bluestreak and mutants which affect pole cell migration implicates Bluestreak in this process. Finally, I found that Blue localizes to centrosomes along with [gamma]-tubulin throughout the embryo, and to the nuclear membrane in pole cells. My findings introduce the possibility that Bluestreak may act to regulate germ cell migration in Drosophila.Item Regional and temporal analysis of sulfate labelled glycosaminoglycans during chick cardiac mesenchyme formation and migration(Texas Tech University, 1983-05) Funderberg, Fiona MargaretNot availableItem Regulation by phytoestrogens of migration, actin cytoskeleton, and signaling cascades relevant to cancer cell motility(2006-05) Azios, Nicolas Gabriel; Roux, Stanley J.; Dharmawardhane, Surangani F.Genistein, daidzein, and resveratrol are polyphenolic plant compounds called phytoestrogens (PEs) because they are capable of binding and activating estrogen receptor (ER) isoforms due to structural similarity to estrogen (E2). The central hypothesis governing these investigations is that PEs can bind to plasmamembrane ERs, cross-talk with epidermal growth factor receptor (EGFR), and signal downstream to an array of molecular pathways including those involved in cell motility. This is relevant to breast cancer metastasis as PEs have been shown to have both preventative and promotional effects on breast cancer cells. The data herein investigates the role of E2, genistein, daidzein, and resveratrol in cell migration, actin cytoskeleton organization, focal adhesion assembly, as well as EGFR, focal adhesion kinase (FAK), and Rho family GTPase activation in ER (+/-) human breast cancer cells. We report that E2 and EGF increase cell migration, induce Rac-dependent lamellipodia formation, increase focal adhesion assembly, and increase EGFR, FAK, and Rac activity in ER[beta] (+) cells. We report that genistein and daidzein also increase cell migration, Rac-dependent lamellipodia formation, focal adhesion assembly, and FAK activity in ER[beta] (+) cells. Resveratrol demonstrates a biphasic concentration-dependent effect on the same signaling pathways. Resveratrol at 5 [micromolar] increases cell migration, lamellipodia formation, and increases FAK and Rac activity in ER[beta] (+) cells similar to E2. Conversely, resveratrol at 50 [micromolar] inhibits cell migration/invasion, blocks E2/EGFinduced migration, induces sustained and unpolarized filopodia, decreases focal adhesion assembly, increases EGFR activity, and decreases FAK, Cdc42, and Rac activity in ER[beta] (+) cells. The induction of filopodia by 50 [micromolar] resveratrol is partially Rho GTPaseindependent and can be observed in serum and on extracellular matrices. The induction by 50 [micromolar] resveratrol of a global, sustained extension of filopodia in conjunction with inhibition of focal adhesion assembly, as well as FAK, Cdc42, and Rac activity is hypothesized to negatively affect breast cancer cell motility. Ultimately, the elucidation of these cell structures and signaling mechanisms in response to PEs will help to determine a preventive or promotional role for plant compound-based therapies in breast cancer metastasis.