ZMB Member Shirley Knauer, Research
Prof. Dr. Shirley Knauer
Mitosis and Apoptosis
Ordered development and cellular homeostasis rely on proper mitosis and controlled apoptosis. Dysregulation of any of these processes may not only result in developmental defects but may also lead to a variety of pathological outcomes, such as cancer.
In eukaryotic cells, an important mechanism to control the cellular localization and function of proteins involved in these processes is active nucleo-cytoplasmic transport. These processes takes place through the nuclear pore complex and are regulated by specific signals and transport factors. Nuclear import is mediated by nuclear import signals (NLS), which interact with import receptors in the cytoplasm. Nuclear export signals (NESs) are leucine-rich, interact with the export receptor Crm1 in the nucleus and depend on the small GTPase Ran, which controls the Crm1/substrate interaction.
The Dual Role of the Inhibitor of Apoptosis Protein (IAP) Survivin
Fresh data from our group now provide evidence that the dual activity of Crm1 as an export receptor and a mitotic regulator is directly linked to the tumor promoting role of the inhibitor of apoptosis protein Survivin. Survivin is highly expressed in most cancers and proposed to function as a mitotic regulator and an apoptosis inhibitor. Importantly, Survivin’s expression has been correlated with resistance against cancer therapy-induced apoptosis and abbreviated patient survival, and hence is regarded a bona fide therapeutic target.
Chromosomal Passenger Proteins
By applying innovative microscopic techniques and computer-guided microinjection in living cells, we could show that Survivin can shuttle between the nucleus and the cytoplasm, and Crm1’s function as an export receptor creates an increased cytoplasmic Survivin concentration. This pronounced cytoplasmic localization seems to promote Survivin’s cytoprotective activity by facilitating the interplay with the apoptotic machinery. During mitosis, the Crm1/Survivin interaction is critically involved in tethering the CPC to the centromeres and thus, ensures proper chromosome segregation.
Clinical Relevance and Therapeutic Potential
These findings appear to be of clinical relevance since preferential nuclear localization of Survivin, indicative of disturbed nuclear export, turned out to be a statistically highly significant favorable prognostic marker in cancer patients. Since the Survivin ‘network’ is exploited in virtually every human cancer, our data combined with our cell based screening assays emphasize to exploit the pharmacogenetic interference with Survivin’s export as a novel therapeutic strategy. Whether a Survivin-tailored export inhibition for cancer cells will be effective in inhibiting Survivin's cancer promoting functions in somatic cancer cells, tumor stromal, endothelial and cancer stem cells, are the challenges for the future.