Thesis supervisor: David R. Sheff. Includes bibliographic references (p. 84-93).

Thesis (Ph. D.)--University of Oregon, 2006. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 76-86). Also available for download via the World Wide Web; free to University of Oregon users.

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Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2010-2011 / La protéine de l'adénovirus humain E4orf4 (Early region 4 open reading frame 4) induit un programme de MC programmée indépendant des caspases chez les cellules transformées et cancéreuses. Des données indiquent qu'E4orf4 pourrait fournir un outil moléculaire pour obtenir des connaissances plus approfondies sur la façon de manipuler les fonctions oncogéniques afin d'induire sélectivement le suicide des cellules cancéreuses. Les travaux du laboratoire indiquent que la cytotoxicité d'E4orf4 repose sur sa capacité à perturber le trafic des endosomes de recyclage (ERs) via l'action concertée des kinases de la famille Src (KFS), de la RhoGTPase Cdc42 et de l'actine. Ces perturbations stimulent le transport des ERs dirigés par Rab11a vers le trans-Golgi et la fragmentation du Golgi, laquelle contribue à la progression de la MC. Les travaux présentés dans ce mémoire visent à déterminer la contribution de cette nouvelle voie de signalisation (contrôlant le trafic des ERs) dans le remodelage des organites en réponse au stress. Pour ce faire, la staurosporine (STS), un inhibiteur de kinases à large spectre induisant plusieurs mécanismes de MC, a été utilisé comme modèle principal. Les résultats indiquent que la STS perturbe le trafic des ERs et stimule leur translocation vers les membranes du trans-Golgi, lesquelles sont subséquemment fragmentées. Ces évènements sont indépendants des caspases et contribuent à la MC. En outre, la mobilisation des ERs induite par la STS est médiée par les KFS, Cdc42 et l'actine, tout comme la fragmentation du Golgi. De plus, j'ai démontré que la fragmentation du Golgi induite par la STS en absence de caspases contrôle partiellement la fission apoptotique des mitochondries, une organelle ayant un rôle central dans la signalisation de plusieurs modes de MC. Finalement, j'ai évalué la contribution de cette voie de transport rétrograde à l'activation des caspases. Les résultats préliminaires suggèrent que les GTPases Rab11a et Cdc42 jouent un rôle en amont de l'activation des caspases effectrices. Nous proposons que les signaux de stress stimulent la mobilisation des ERs, lesquels pourraient délivrer des lipides et des protéines de signalisation contribuant au remodelage des organelles et à la communication inter-organites orchestrant l'activation de multiples mécanismes de MC, tout au moins, dans le contexte de cellules cancéreuses.

Laminin binding integrins 6 (CD49f) and 3 (CD49c) are persistently but differentially expressed in prostate cancer (PCa). Integrin internalization is an important determinant of their cell surface expression and function. Using flow cytometry, and first order kinetic modeling, we quantitated the intrinsic internalization rates of integrin subunits in a single cycle of internalization. In PCa cell line DU145, 6 integrin internalized with a rate constant (k(actual)) of 3.25min(-1), threefold faster than 3 integrin (1.0min(-1)), 1.5-fold faster than the vitronectin binding v integrin (CD51) (2.2min(-1)), and significantly slower than the unrelated transferrin receptor (CD71) (15min(-1)). Silencing of 3 integrin protein expression in DU145, PC3, and PC3B1 cells resulted in up to a 1.71-fold increase in k(actual) for 6 integrin. The internalized 6 integrin was targeted to early endosomes but not to lamp1 vesicles. Depletion of 3 integrin expression resulted in redistribution of 64 integrin to an observed cell-cell staining pattern that is consistent with a suprabasal distribution observed in epidermis and early PIN lesions in PCa. Depletion of 3 integrin increased cell migration by 1.8-fold, which was dependent on 61 integrin. Silencing of 6 integrin expression however, had no significant effect on the k(actual) of 3 integrin or its distribution in early endosomes. These results indicate that 3 and 6 integrins have significantly different internalization kinetics and that coordination exists between them for internalization. J. Cell. Biochem. 118: 1038-1049, 2017.

Thesis (Ph. D.)--Rutgers University, 2010. / "Graduate Program in Cell and Developmental Biology." Includes bibliographical references (p. 292-304).

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2003. / Vita. Bibliography: 160-180.

Thesis (Ph. D.)--University of Missouri-Columbia, 2005. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (November 7, 2006) Vita. Includes bibliographical references.

Laminin binding integrins (α6β1 and α3β1) are persistently but differentially expressed throughout prostate cancer progression and metastasis. Prostate cancer primarily invades through laminin rich nerve for extracapsular escape during cancer metastasis. An intense expression of the pro-metastatic α6 integrin was observed during perineural invasion with a heterogeneous distribution of the integrin on the cancer cell membrane as well as intracellularly. Bone and soft tissue metastasis of human prostate cancer demonstrated a similar pattern where 75-80% of the cancers had significant intracellular staining. This was correlated with an mRNA overexpression of various intracellular trafficking regulators. Using a prostate cancer cell culture model of DU145 cells, the α6 integrin was found to be constitutively internalized in cancer cells at a rate of 3.25 min-1, which was 3 fold greater than internalization rate of α3 integrin, classically considered a "non-circulating" receptor. α6 and α3 integrins function coordinately to regulate cell migration during development, wound healing. Their orchestrated redistribution during these processes is well-known, but the mechanism remains elusive. Current study identifies intracellular trafficking of these integrins as a key mechanism of their coordination. Depletion of α3 integrin in prostate cancer cells significantly increased internalization of α6 integrin up to 1.7-fold and increased localization of α6 integrin at cell-cell membrane locations. There was a concomitant 1.8-fold increase in cell migration significantly dependent on α6 integrin. Depletion of α6 integrin expression however, had no effects on the internalization of α3 integrin indicating that the identified coordination was unidirectional. α6 integrin trafficking drives cancer invasion, but its selective regulators are unknown. Here, Rab11FIP5 was identified as a selective regulator of α6 integrin recycling to cell membrane. Interestingly, α6 integrin was found to be primarily recycled to the cell-cell membranes where it colocalized with Rab11 and Rab11FIP5. Depletion of Rab11FIP5 reduced such membrane expression of α6 integrin, inhibited cell-cell cohesion in 3D culture and significantly reduced cell migration. The localization of α6 and α3 integrin at these locations have been implicated in cell adhesion. Based on current study α6 recycling by Rab11FIP5 might be key to such function. Another Rab11 effector protein Rab11FIP1 was identified as a regulator of both α3 and α6 integrin trafficking. Depletion of Rab11FIP1 reduced membrane expression of α3 integrin by significantly increasing its internalization and reducing the recycling. There was a major effect on α6 integrin internalization, which increased to an extent similar to that observed on α3 integrin depletion. Rab11FIP1 regulated α6 integrin recycling, in a pathway found to be independent of Rab11FIP5. Taken together, current research defined Rab11FIPs as regulators of α6 and α3 integrins. A unidirectional coordination between α6 and α3 integrin was identified such that loss of α3 integrin, representative of high grade prostate cancer, amplifies integrin α6 integrin internalization and a resultant migratory phenotype.

The present study was undertaken to establish the mechanism(s) involved in the endocytic pathway, in particular, early endosome processing and delivery to the lysosomes. Two models for endosome processing have previously been proposed in the literature, namely the maturation and vesicular traffic models. The general consensus has been an early phase of intermingling of the endocytic contents markers within early endosomes that mature to form non-fusogenic late endosomes (maturation model). This maturation phase is followed by a segregation phase where intermingling of contents between vesicles no longer takes place. To establish the mechanism(s) involved in early endosome processing and delivery to lysosomes, a kinetic analysis was made using results from cellular fluid-phase uptake assays. This unique approach offers an alternative view to previous studies on the mechanisms in operation during endocytic processing. The results and conclusions made could thus confirm or disprove previously proposed mechanisms.