Characterization of the cellular functions of the nucleoporins Nup153 and Nup88

Abstract

Characterization of the Cellular Functions of the Nucleoporins Nup153 and Nup88 PhD Thesis, Yvonne Christine Lussi, 2010, University of Basel Nuclear pore complexes (NPCs) and nuclear lamins are major constituents of the nuclear envelope (NE) in metazoan cells. NPCs are embedded in the NE and they mediate all nucleocytoplasmic transport events. NPCs are built of around 30 nucleoporins, which, besides being involved in nuclear transport, have been shown to be engaged in a number of other cellular processes, such as transcriptional regulation, kinetochore organization and cell division. Here, we provide an analysis of Nup153 function in mitosis in Chapter 2. We show that overexpression and deletion of Nup153 leads to mitotic defects due to a misregulation of the spindle assembly checkpoint protein Mad1. In Chapter 3, we identify Nup88 as novel lamin A-binding protein. Using interaction assays and immunofluorescence microscopy, we characterize the direct interaction of Nup88 with lamin A. We show that the interaction of lamin A with Nup88 is mediated by the lamin A Ig-fold, and that the interaction between the two proteins is abrogated in the presence of laminopathy-associated mutations lying in the Ig-fold domain of lamin A. Finally, in Chapter 4, we show that Nup88 is implicated in cell cycle regulation due to an interaction with the lamin A-LAP2α complex. Our results presented in this thesis contribute to broaden the current knowledge of cellular functions of the nucleoporins Nup153 and Nup88, as well as to increased understanding of the interaction of nucleoporins with the nuclear lamina and the impact of laminopathy-associated mutations on the interaction of lamin A with Nup88. The finding that Nup88 is involved in gene regulation and proliferation is a key step in understanding Nup88’s implication in cancer development.