The nuclear pore complex (NPC) is the gateway to and from the genome. The work presented in this thesis is the result of the investigations towards understanding some of the key questions affecting NPC biology: How is the NPC built up? Can we dissect different modes of transport at the level of the NPC? Does the NPC play a role in the development of cancer? Several findings presented in this thesis have contributed to the current knowledge of the biology of the Nuclear Pore Complex. Structurally, the hierarchy towards incorporation to the NPC of the cytoplasmic components Nup88, Nup214 and Nup 358 and their relevance to nuclear transport has been established. Concerning nuclear transport itself, a supporting role in CRM1-mediated export has been assigned to Nup358 and an explanation to the weak nature of the interaction of CRM1 and its NES-containing cargoes been elucidated. This work has amplified as well the concept of nuclear translocation by creating a distinction in transport pathways that, instead of been exclusively dependent on the receptor-NPC and the receptor-cargo interactions, consider the characteristics of the cargo itself. In fact , while showing cargos that can be exported by CRM1 independently of Nup214, we present first in vivo evidence of the implication of Nup214 in a NPC gating mechanism for the CRM1-dependent export of preribosomes Furthermore, this result excludes any implication of the strong CRM1 binding Nup214 FG-domain in this mechanism and in other suggested models of CRM1 export. Finally, this thesis has provided information concerning the localization and stability of the aberrant product Nup214-ABL that may be of great value for the development of alternative therapies of leukemic diseasesUBL - phd migration 201
