Thesis (M. Phil.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 77-100). Also available in print.

Septins are a family of GTP-binding proteins implicated in mammalian cell division. Since these proteins form heterologous complexes and filaments in interphase cells, it has been assumed that depletion of any or all septins in a given cell type will give rise to the same phenotype. I demonstrate that while all septins expressed in HeLa cells localize to the cleavage furrow and midbody during cytokinesis, and co-immunoprecipitate throughout cell division, they do not all have identical roles during this process. Specific depletion of SEPT2 or SEPT11 caused defects in the early stages of cytokinesis, ultimately resulting in binucleation. Similar results were observed upon simultaneous depletion of all septins. In sharp contrast, SEPT9 was dispensable for the early stages of cell division, but was critical for the final separation of daughter cells. I demonstrate that SEPT9 mediates the localization of the vesicle-tethering exocyst complex to the midbody. Immunofluorescence microscopy suggests that SEPT9 may act to compartmentalize the exocyst at the site of abscission, analogous to the role performed by septins in Saccharomyces cerevisiae. I provide evidence that the N-terminal region of SEPT9, which is absent from the shorter SEPT9 isoforms, plays an important role in abscission. I describe a long-anticipated link between a mammalian septin and the cell cycle machinery by showing that the N-terminal region of SEPT9 is phosphorylated at threonine 24 upon mitotic entry by cyclin-dependent kinase 1. This creates a binding site for the WW domain of the peptidyl-prolyl isomerase Pin1. I provide evidence that Pin1 induces a conformational change in the N-terminal region of SEPT9 that is important for the completion of cytokinesis. I propose that mitotic regulation of SEPT9 by Cdk1 and Pin1 regulates an interaction between SEPT9 and an unidentified protein that is critical for abscission.

Septins are a family of GTP-binding proteins implicated in mammalian cell division. Since these proteins form heterologous complexes and filaments in interphase cells, it has been assumed that depletion of any or all septins in a given cell type will give rise to the same phenotype. I demonstrate that while all septins expressed in HeLa cells localize to the cleavage furrow and midbody during cytokinesis, and co-immunoprecipitate throughout cell division, they do not all have identical roles during this process. Specific depletion of SEPT2 or SEPT11 caused defects in the early stages of cytokinesis, ultimately resulting in binucleation. Similar results were observed upon simultaneous depletion of all septins. In sharp contrast, SEPT9 was dispensable for the early stages of cell division, but was critical for the final separation of daughter cells. I demonstrate that SEPT9 mediates the localization of the vesicle-tethering exocyst complex to the midbody. Immunofluorescence microscopy suggests that SEPT9 may act to compartmentalize the exocyst at the site of abscission, analogous to the role performed by septins in Saccharomyces cerevisiae. I provide evidence that the N-terminal region of SEPT9, which is absent from the shorter SEPT9 isoforms, plays an important role in abscission. I describe a long-anticipated link between a mammalian septin and the cell cycle machinery by showing that the N-terminal region of SEPT9 is phosphorylated at threonine 24 upon mitotic entry by cyclin-dependent kinase 1. This creates a binding site for the WW domain of the peptidyl-prolyl isomerase Pin1. I provide evidence that Pin1 induces a conformational change in the N-terminal region of SEPT9 that is important for the completion of cytokinesis. I propose that mitotic regulation of SEPT9 by Cdk1 and Pin1 regulates an interaction between SEPT9 and an unidentified protein that is critical for abscission.

Errata pasted onto back page. / Bibliography: p. 133-149. / 149 p., [29] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The RhoGEF activity of PBL is shown to be acting predominantly by the activation of Rho1 and downstream signaling pathways required for contractile ring function during cytokinesis. Genetic evidence suggests this could be through the activation of Diaphanous (an FH protein) to reorganize the actin cytoskeleton, as well as through the activation of Rho-kinase which results in the phosphorylation, and activation of myosin. Highlights a possible role for PBL during contractile ring function at a later stage that previously thought. Genetic interaction screens were employed to identify regulators of PBL activity during cytokinesis. CDK1 was identified genetically as a candidate for regulating PFB activity, but functional studies in vivo showed that this regulation was not by direct phophorylation of the PBK consensus CDK1 suites tested. Further screening has identified other possible components pf PBL signaling pathways, but a role during cytokinesis for these interactors remains to be confirmed. The eye phenotypes described provide ideal systems for the identification of components of PBL signaling pathways in Drosophila. The high level of conservation in the mechanism of cytokinesis from yeast to mammals would also suggest that the identified interactors would most likely represent components of cytokinesis pathways in all eukaryotes. / Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2002?

Thesis (Ph.D.)--University of Adelaide, Dept. of Genetics, 1998. / Errata is pasted onto back end paper. Includes bibliographical references (26 leaves).

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 192-206). Also available in electronic version. Access restricted to campus users.

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 111-120). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 111-120). Also available on the Internet.

京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第20530号 / 生博第372号 / 新制||生||49(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 松田 道行, 教授 井垣 達吏, 教授 HEJNA,James / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

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