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Focal adhesion kinase mediates caveo...

Bailey, Kelly M.

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Focal adhesion kinase mediates caveolin-1 expression during epithelial to mesenchymal transition: A novel pathway regulating aspects of cell motility in cancer.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Focal adhesion kinase mediates caveolin-1 expression during epithelial to mesenchymal transition: A novel pathway regulating aspects of cell motility in cancer./
Author:	Bailey, Kelly M.
Description:	239 p.
Notes:	Source: Dissertation Abstracts International, Volume: 69-09, Section: B, page: 5141.
Contained By:	Dissertation Abstracts International69-09B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3328516
ISBN:	9780549814757

Focal adhesion kinase mediates caveolin-1 expression during epithelial to mesenchymal transition: A novel pathway regulating aspects of cell motility in cancer.
Bailey, Kelly M.

Focal adhesion kinase mediates caveolin-1 expression during epithelial to mesenchymal transition: A novel pathway regulating aspects of cell motility in cancer. - 239 p.

Source: Dissertation Abstracts International, Volume: 69-09, Section: B, page: 5141.

Thesis (Ph.D.)--West Virginia University, 2008.

This item is not available from ProQuest Dissertations & Theses.

Caveolin-1, the protein coat of caveolae membrane invaginations, was originally hypothesized to function solely as a tumor suppressor in human cancers. However, since the early 1990s, caveolin-1 has been found to be up-regulated in a number of metastatic cancers. This expression has been shown to correlate with disease progression and decreases in overall patient survival in some tumor types. Further, caveolin-1 expression is elevated in multi-drug resistant cancer cells and caveolae are thought to participate in the efflux pathway to pump drugs out of these tumor cells. The overall goal of these studies was to examine changes in and regulation of caveolin protein expression in a key step of tumor metastasis, the epithelial to mesenchymal transition. Further, we aimed to determine the functional ramifications of caveolin-1 expression on aspects of cell polarization, migration, and invasion.

ISBN: 9780549814757Subjects--Topical Terms:

3172791
Cellular biology.

Focal adhesion kinase mediates caveolin-1 expression during epithelial to mesenchymal transition: A novel pathway regulating aspects of cell motility in cancer.
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020 $a 9780549814757
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100 1 $a Bailey, Kelly M. $3 3179596
245 1 0 $a Focal adhesion kinase mediates caveolin-1 expression during epithelial to mesenchymal transition: A novel pathway regulating aspects of cell motility in cancer.
300 $a 239 p.
500 $a Source: Dissertation Abstracts International, Volume: 69-09, Section: B, page: 5141.
500 $a Adviser: Scott Weed.
502 $a Thesis (Ph.D.)--West Virginia University, 2008.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a Caveolin-1, the protein coat of caveolae membrane invaginations, was originally hypothesized to function solely as a tumor suppressor in human cancers. However, since the early 1990s, caveolin-1 has been found to be up-regulated in a number of metastatic cancers. This expression has been shown to correlate with disease progression and decreases in overall patient survival in some tumor types. Further, caveolin-1 expression is elevated in multi-drug resistant cancer cells and caveolae are thought to participate in the efflux pathway to pump drugs out of these tumor cells. The overall goal of these studies was to examine changes in and regulation of caveolin protein expression in a key step of tumor metastasis, the epithelial to mesenchymal transition. Further, we aimed to determine the functional ramifications of caveolin-1 expression on aspects of cell polarization, migration, and invasion.
520 $a In the first study, we further explored a past observation made by our lab and others: Caveolin-1 is tightly polarized at the cell rear during directional migration. As caveolin-1 KO cells are also deficient in caveolin-2 expression, we first used an siRNA approach to determine that caveolin-2 is not critical to cell motility. Then, using cell immunofluorescence techniques, we examined the distribution of a number of proteins and cholesterol in polarized cells. We found that caveolin-1 is an important regulator of the cell rear membrane composition, specifically of caveolae components such as GM1 and cholesterol. We also attempted to identify novel polarized proteins using mass spectrometry analysis, however, due to method limitations, this approach ultimately failed. Our data from this study also suggests that cytoskeletal components such as actin, myosin II, and filamin can alter caveolin-1 polarization. Through the data collected in both Study 1 and 3, we hypothesize that the actin-crosslinking protein filamin may actually be the factor responsible for the rear polarization of caveolin-1. Future goals of the lab are to address this hypothesis in order to better understand caveolin distribution in both spread and polarized cells.
520 $a In Study 2, we specifically looked at changes in caveolin-1 expression during the epithelial to mesenchymal transition (EMT). Caveolin-1 appears to be up-regulated as a product of EMT, as changes in its expression occur following alterations in cell morphology and the expression of some known EMT markers. Further, with the methods and cell lines we examined, we could not find a role for caveolin-1 in EMT progression per se. However, as examined in Study 3, caveolin-1 expression appears to play an important role in the ability of cells that have undergone EMT to effectively migrate and/or invade. By using the novel FAK inhibitor PF-228, we were able to show that FAK can regulate caveolin-1 expression during the epithelial to mesenchymal transition. Along these lines, different factors (such as EGF or TGF-beta1) can trigger EMT and do so through different basic cell signaling pathways; however, changes in caveolin-1 expression are still correlated with changes in FAK. Our results also show that Src can contribute to the regulation of caveolin-1 expression, however, only in the presence of FAK.
520 $a As mentioned, in the third and final study, we explored the functional ramifications of caveolin-1 expression. By using Electric Cell-Substrate Impedence Sensing assays, we found that cells with a knock-down of caveolin-1 show large increases in attachment resistance compared to caveolin expressing WT controls. Upon manual quantification of immunofluorescently labeled cells, we found that caveolin knock-down cells demonstrate both increases in total cell spreading area and total number of focal adhesions. Phospho-caveolin-1 may contribute to this focal adhesion effect, but cannot explain all of the noted changes in cell spreading. Similarly, caveolae (or caveolin-1 regulation of cholesterol distribution) also do not appear to account for this effect, as cell treatment with methyl-beta cyclodextran could not account for these changes in cell behavior. Interestingly, FAK KO cells and WT cells treated with the FAK inhibitor PF-228 show increases in cell spreading and total number of focal adhesions and have greatly reduced caveolin-1 expression. Based on our ECIS data, it is possible that this lack of caveolin-1 could contribute to the phenotype of cells with a knock-down or inhibition of FAK.
520 $a In summary, these studies show a novel pathway through which FAK can regulate aspects of cell motility (i.e. by regulating caveolin-1 expression). Tumors utilizing this pathway could be treated with inhibitors such as PF-228 or similar pharmaceuticals in an attempt to hamper cell motility and potentially reduce cell metastasis. Future goals in the lab could be to address this true potential of inhibiting this pathway to reduce metastasis in vivo. .
590 $a School code: 0256.
650 4 $a Cellular biology. $3 3172791
650 4 $a Oncology. $3 751006
690 $a 0379
690 $a 0992
710 2 $a West Virginia University. $3 1017532
773 0 $t Dissertation Abstracts International $g 69-09B.
790 $a 0256
791 $a Ph.D.
792 $a 2008
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3328516