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Publication Date

2007-06-27

Availability

UM campus only

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2007-04-10

First Committee Member

Sandra Lemmon - Committee Chair

Second Committee Member

Beatriz Fontoura - Committee Co-Chair

Third Committee Member

Lawrence H. Boise - Committee Member

Fourth Committee Member

Kerry Burnstein - Committee Member

Fifth Committee Member

Joachim Seemann - Outside Committee Member

Abstract

Nucleoporins mediate nucleocytoplasmic trafficking in interphase. In mitosis, upon nuclear envelope breakdown, the role and regulation of Nups remain to be elucidated. An important subcomplex of nucleoporins is the Nup107-160 complex, which, in mitosis, is involved in spindle assembly and nuclear pore re-assembly. Here we show that the level of a key constituent of the Nup107-160 complex- Nup96 is cell cycle regulated. We found that the mechanism involved in regulating Nup96 levels in mitosis is proteolysis by the anaphase-promoting complex (APC). Nup96 interacts with the APC, and its proteolysis can be regulated by Cdc20 and Cdh1. Like the Nup107-160 complex, the APC is localized at kinetochores, centrosomes, and spindles. Disruption of Nup96 levels led to an acceleration of prophase to prometaphase transition and, most importantly, resulted in a delay of G1 progression. Thus, regulation of Nup96 proteolysis in mitosis sets the stage for proper G1 progression. Additionally, we have observed differential regulation of members of the Nup107-160 complex during mitosis and have identified interacting partners of Nup96 at the centrosome which reveal a novel role of nucleoporins in regulating microtubule nucleation.

Keywords

Mitosis; Microtubule Nucleation; Nucleoporins

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