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The Role of TM9SF4 in Cytoskeleton R...

Meng, Zhaoyue.

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The Role of TM9SF4 in Cytoskeleton Rearrangement.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Role of TM9SF4 in Cytoskeleton Rearrangement./
作者:	Meng, Zhaoyue.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	369 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-08, Section: B.
Contained By:	Dissertations Abstracts International80-08B.
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13837874
ISBN:	9780438851726

The Role of TM9SF4 in Cytoskeleton Rearrangement.
Meng, Zhaoyue.

The Role of TM9SF4 in Cytoskeleton Rearrangement. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 369 p.

Source: Dissertations Abstracts International, Volume: 80-08, Section: B.

Thesis (Ph.D.)--The Chinese University of Hong Kong (Hong Kong), 2018.

This item must not be sold to any third party vendors.

TM9SF4 belongs to the transmembrane 9 superfamily, which has nine putative trans-membrane domains and a large non-cytoplasmic N-terminus. This family is highly conserved through evolution. It has been found that TM9SF4 is involved in phagocytosis in D. discoideum and Drosophila. Besides, the expression level of TM9SF4 is upregulated in cancer cells and it may contribute to cancer cell invasion and cannibalism. However, the functional mechanism of TM9SF4 is largely unknown. In the present study, I found that TM9SF4 is mainly localized in Golgi apparatus but could also be detected in endosome, lysosome and cell protrusions in certain cell types. My results confirmed that TM9SF4 is highly expressed in many types of cancer cell lines such as ovarian cancer cell line A2780 whereas its expression level is much lower in some noncancerous cell lines such as the fibroblast cell line NIH3T3. Knockdown of TM9SF4 in A2780 cells largely decreased the cell viability and induced a dramatic alteration in cell morphology displayed as increased stress fiber formation and enlarged cell size. Actin was identified to be one of the major interacting proteins with TM9SF4. Co-immunoprecipitation assay showed that the N-terminal fragment functions as the active part of TM9SF4 to bind actin. In vitro actin binding assay demonstrated that TM9SF4_N258 could directly bind to F-actin and the LKXXE motif in TM9SF4 N-terminus is responsible for its actin binding ability. Actin depolymerization assay indicated that TM9SF4_N258 itself has no obvious effect on F-actin depolymerization but it can effectively promote cofilin mediated actin severing. TM9SF4_N258-GFP overexpression in NIH3T3 cells induced dramatic cytoskeleton alteration as decreased cell size and actin stress fiber disruption which was opposite to that of TM9SF4 knockdown effect in A2780 cells, and such phenotype was abolished by cofilin knockdown. This further proved that cofilin is required for TM9SF4-induced actin depolymerization. The mechanism by which TM9SF4 promotes cofilin's severing of actin filaments was then investigated. It was found that TM9SF4 is a copper dependent redox protein which could induce actin S-glutathionylation on Cys374. Such modification would change the tertiary structure of actin and make it more susceptible to cofilin-mediated severing. TM9SF4 induced actin S-glutathionylation plays an important role in cell adhesion and motility. Knockdown of TM9SF4 could enhance cancer cell adhesion and reduce cell motility. My results also showed that TM9SF4 is involved in F-actin aggresome formation in A2780 cells. TM9SF4 depletion impedes F-actin aggregates clearance due to unsuccessful F-actin aggresome formation and subsequently inhibition in cofilin activation and autophagy-lysosome degradation pathway. In addition, TM9SF4 is also involved in cancer cell cytokinesis. TM9SF4 suppression causes the formation of multinuclear cells with defective cytokinesis. Taken together, my results provide a novel pathway of F-actin depolymerization and sheds new light on the mechanisms about how cofilin mediated actin severing becomes more rapid and efficient in cellular behaviors. Moreover, knockdown of TM9SF4 could decrease the cancer cell viability and metastasis through several actin-related ways. Therefore, specific TM9SF4 inhibitors may serve as potential therapeutic option to control cancer growth and metastasis.

ISBN: 9780438851726Subjects--Topical Terms:

3172791
Cellular biology.

The Role of TM9SF4 in Cytoskeleton Rearrangement.
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500 $a Source: Dissertations Abstracts International, Volume: 80-08, Section: B.
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506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a TM9SF4 belongs to the transmembrane 9 superfamily, which has nine putative trans-membrane domains and a large non-cytoplasmic N-terminus. This family is highly conserved through evolution. It has been found that TM9SF4 is involved in phagocytosis in D. discoideum and Drosophila. Besides, the expression level of TM9SF4 is upregulated in cancer cells and it may contribute to cancer cell invasion and cannibalism. However, the functional mechanism of TM9SF4 is largely unknown. In the present study, I found that TM9SF4 is mainly localized in Golgi apparatus but could also be detected in endosome, lysosome and cell protrusions in certain cell types. My results confirmed that TM9SF4 is highly expressed in many types of cancer cell lines such as ovarian cancer cell line A2780 whereas its expression level is much lower in some noncancerous cell lines such as the fibroblast cell line NIH3T3. Knockdown of TM9SF4 in A2780 cells largely decreased the cell viability and induced a dramatic alteration in cell morphology displayed as increased stress fiber formation and enlarged cell size. Actin was identified to be one of the major interacting proteins with TM9SF4. Co-immunoprecipitation assay showed that the N-terminal fragment functions as the active part of TM9SF4 to bind actin. In vitro actin binding assay demonstrated that TM9SF4_N258 could directly bind to F-actin and the LKXXE motif in TM9SF4 N-terminus is responsible for its actin binding ability. Actin depolymerization assay indicated that TM9SF4_N258 itself has no obvious effect on F-actin depolymerization but it can effectively promote cofilin mediated actin severing. TM9SF4_N258-GFP overexpression in NIH3T3 cells induced dramatic cytoskeleton alteration as decreased cell size and actin stress fiber disruption which was opposite to that of TM9SF4 knockdown effect in A2780 cells, and such phenotype was abolished by cofilin knockdown. This further proved that cofilin is required for TM9SF4-induced actin depolymerization. The mechanism by which TM9SF4 promotes cofilin's severing of actin filaments was then investigated. It was found that TM9SF4 is a copper dependent redox protein which could induce actin S-glutathionylation on Cys374. Such modification would change the tertiary structure of actin and make it more susceptible to cofilin-mediated severing. TM9SF4 induced actin S-glutathionylation plays an important role in cell adhesion and motility. Knockdown of TM9SF4 could enhance cancer cell adhesion and reduce cell motility. My results also showed that TM9SF4 is involved in F-actin aggresome formation in A2780 cells. TM9SF4 depletion impedes F-actin aggregates clearance due to unsuccessful F-actin aggresome formation and subsequently inhibition in cofilin activation and autophagy-lysosome degradation pathway. In addition, TM9SF4 is also involved in cancer cell cytokinesis. TM9SF4 suppression causes the formation of multinuclear cells with defective cytokinesis. Taken together, my results provide a novel pathway of F-actin depolymerization and sheds new light on the mechanisms about how cofilin mediated actin severing becomes more rapid and efficient in cellular behaviors. Moreover, knockdown of TM9SF4 could decrease the cancer cell viability and metastasis through several actin-related ways. Therefore, specific TM9SF4 inhibitors may serve as potential therapeutic option to control cancer growth and metastasis.
590 $a School code: 1307.
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710 2 $a The Chinese University of Hong Kong (Hong Kong). $b Cell and Molecular Biology. $3 3435042
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793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13837874