Analysis of the Nup214-CRM1 interaction in nuclear protein export

• Applicant: Professor Dr. Ralph Kehlenbach
• Subject Area: Cell Biology
• Term: from 2009 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 97688438

The nucleoporin Nup214, a component of the nuclear pore complex, was initially identified as a potential oncogene in a fusion with other proteins. Very recently, Nup214 was found to be mutated in breast cancer tumor cells at a rate that justified its classification as a “cancer gene”. Nup214 is known to play a role in nucleocytoplasmic transport, nothing is known, however, about possible mechanisms that would promote tumorigenesis as a result of mutated Nup214. An attractive hypothesis, which is supported by published work from us and others, is that Nup214 is required for nuclear export of selected proteins with links to growth control. One such candidate is the transcription factor NFAT (nuclear factor of activated T cells), whose CRM1-dependent export requires Nup214. Here we propose to investigate the function of Nup214 in light of a possible involvement in tumorigenesis, where nuclear export of a subset of proteins might be inhibited. For our analysis, we will use our established protocols to deplete Nup214 by RNA-interference. Furthermore, we will take advantage of transport factors from the model organism C. elegans to analyze the requirements for the interaction between CRM1, the nucleoporin and an export cargo. Finally, we will analyze mutations/deletions in Nup214 and their possible consequences for nuclear transport of NFAT and other cargo proteins in the context of breast cancer cells. Together, we hope to enhance our understanding of the function of Nup214 under physiological as well as pathological conditions. -

• DFG Programme: Research Grants