The role of bidirectional nucleocytoplasmic transport in apoptosis.
Chan, Kheng Sze.
Date of Issue2011
School of Biological Sciences
Apoptosis or programmed cell death 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 I showed that when a cell is under apoptotic stress, the pro-survival 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. My 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.
DRNTU::Science::Biological sciences::Molecular biology