title: Survivin withdrawal by nuclear export failure as a physiological switch to commit cells to apoptosis.
abstract: Apoptosis is a tightly controlled process regulated by many signaling pathways; however, the mechanisms and cellular events that decide whether a cell lives or dies remain poorly understood. Here we showed that when a cell is under apoptotic stress, the prosurvival protein Survivin redistributes from the cytoplasm to the nucleus, thus acting as a physiological switch to commit the cell to apoptosis. The nuclear relocalization of Survivin is a result of inefficient assembly of functional RanGTP-CRM1-Survivin export complex due to apoptotic RanGTP gradient collapse. Subsequently, Survivin undergoes ubiquitination, which not only physically prevents its diffusion back to the cytoplasm but also facilitates its degradation. Together, this spatial and functional regulation of Survivin abolishes its cytoprotective effect toward the apoptotic executors and thus commits a cell to apoptosis. Our data indicate that the withdrawal of Survivin is a novel and active physiological regulatory mechanism that tilts the survival balance and promotes the progression of apoptosis.
authors.affiliation: Division of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore, Singapore.
authors.forename: K-S
authors.initials: KS
authors.lastname: Chan
authors.forename: C-H
authors.initials: CH
authors.lastname: Wong
authors.forename: Y-F
authors.initials: YF
authors.lastname: Huang
authors.forename: H-Y
authors.initials: HY
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism*; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D028884:Karyopherins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000077022:Survivin; D054875:Ubiquitination; D000097606:Exportin 1 Protein
chemical_list: D017228:Hepatocyte Growth Factor; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000077022:Survivin; D000097606:Exportin 1 Protein; C107489:BIRC5 protein, human; C082332:macrophage stimulating protein