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Dissection and modulation of (patho)biological survivin functions by supramolecular ligands ; Analyse und Modulation (patho)biologischer Funktionen von Survivin durch supramolekulare Liganden
Targeted cancer therapy provides a promising approach to fight cancer, the second leading cause of death worldwide following cardiovascular diseases, and reduces or avoids harmful side effects occurring in conventional chemo- and radiotherapy. This therapy addresses specific targets, which are preferentially or exclusively expressed in cancer cells. Survivin, highly up-regulated in almost all cancer types, represents such a target. Its overexpression is associated with resistance against chemo- and radiotherapy, frequent recurrences and decreased patient survival. As a member of the inhibitor of apoptosis protein (IAP) family, Survivin plays a cytoprotective role by inhibiting cell death, but as part of the chromosomal passenger complex (CPC) it is also crucial for the regulation of mitosis. For both biological functions, an interaction with the nuclear export receptor CRM1, mediated by Survivin’s highly conserved, leucine-rich nuclear export signal (NES), is pivotal. However, the mechanisms regulating Survivin’s biological functions are still not completely resolved and a matter of scientific controversy. Thus, interference with the Survivin–CRM1 interaction could not only help to elucidate the distinct biological functions of Survivin but also to potentially inhibit cancer cell proliferation. Small molecule inhibitors of the export receptor CRM1 have already been identified. However, they supposedly also interfere with binding of CRM1 to other NES-bearing proteins, making them at most selective but clearly not specific. Therefore, this work aims to signal-specifically target the NES of Survivin instead of the receptor and thereby to inhibit the interaction between the surface-exposed NES and CRM1 by supramolecular tweezer molecules, which are able to bind to surface-accessible lysine and arginine residues. Establishing a robust protein expression and purification system enabled recombinant production not only of Survivin, but also of the high molecular weight export receptor CRM1 and its cofactor Ran for ...
Dissection and modulation of (patho)biological survivin functions by supramolecular ligands ; Analyse und Modulation (patho)biologischer Funktionen von Survivin durch supramolekulare Liganden
Targeted cancer therapy provides a promising approach to fight cancer, the second leading cause of death worldwide following cardiovascular diseases, and reduces or avoids harmful side effects occurring in conventional chemo- and radiotherapy. This therapy addresses specific targets, which are preferentially or exclusively expressed in cancer cells. Survivin, highly up-regulated in almost all cancer types, represents such a target. Its overexpression is associated with resistance against chemo- and radiotherapy, frequent recurrences and decreased patient survival. As a member of the inhibitor of apoptosis protein (IAP) family, Survivin plays a cytoprotective role by inhibiting cell death, but as part of the chromosomal passenger complex (CPC) it is also crucial for the regulation of mitosis. For both biological functions, an interaction with the nuclear export receptor CRM1, mediated by Survivin’s highly conserved, leucine-rich nuclear export signal (NES), is pivotal. However, the mechanisms regulating Survivin’s biological functions are still not completely resolved and a matter of scientific controversy. Thus, interference with the Survivin–CRM1 interaction could not only help to elucidate the distinct biological functions of Survivin but also to potentially inhibit cancer cell proliferation. Small molecule inhibitors of the export receptor CRM1 have already been identified. However, they supposedly also interfere with binding of CRM1 to other NES-bearing proteins, making them at most selective but clearly not specific. Therefore, this work aims to signal-specifically target the NES of Survivin instead of the receptor and thereby to inhibit the interaction between the surface-exposed NES and CRM1 by supramolecular tweezer molecules, which are able to bind to surface-accessible lysine and arginine residues. Establishing a robust protein expression and purification system enabled recombinant production not only of Survivin, but also of the high molecular weight export receptor CRM1 and its cofactor Ran for ...
Dissection and modulation of (patho)biological survivin functions by supramolecular ligands ; Analyse und Modulation (patho)biologischer Funktionen von Survivin durch supramolekulare Liganden
Bäcker, Sandra (author) / Knauer, Shirley K.
2021-10-26
Theses
Electronic Resource
English
Modulation of Survivin's cancer-promoting functions with supramolecular ligands
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