Trafficking between the nucleus and cytoplasm of the eukaryotic cell is an essential process and a key regulatory point in many cellular functions. The nuclear pore complex is the mediator of all nucleocytoplasmic transport and the precise function of this structure remains a fundamental question in cell biology. Remarkable strides have been made in our knowledge of the nuclear pore and nuclear trafficking over the past decade. Additionally, new paradigms are emerging for the nuclear pore complex, including the surprisingly dynamic nature of this macromolecular structure and unexpected roles for nuclear pore proteins at other sites during mitosis. One component of the nuclear pore, Nup98, serves as a model nucleoporin through which multiple aspects of nuclear pore function can be addressed. The long term goal of the proposed research is an understanding of how nuclear pore complex function is regulated and integrated with other cellular processes. Such integration is particularly relevant for Nup98 which is a target of chromosomal translocations in myelogenous leukemia. It is hypothesized in this proposal that Nup98 serves as a key regulator of nuclear trafficking and nuclear pore function. The specific goals of this proposal are directed at defining the critical interactions through which this nucleoporin contributes to nuclear export and to the structural organization of the nuclear pore complex. Using a combination of biochemical and molecular techniques, live cell dynamics and the Xenopus extract reconstitution system, the intranuclear functions of this dynamic nucleoporin will be assessed and the mechanism coupling nucleoporin dynamics to ongoing transcription will be determined. Further, the role of phosphorylation in regulating the interactions between Nup98 and other nucleoporins will be addressed. Lastly, possible contributions of Nup98 to mitotic functions following disassembly of the nuclear pore complex will be assessed.
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