RAN cycle and cellular senescence

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The small GTPase Ran, Ras-related nuclear protein, plays important roles in multiple fundamental cellular functions such as nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope formation, by binding to either GTP or GDP as a molecular switch. During the long-term culture of normal mammalian cells, I found that the endogenous Ran level gradually reduced in a passage-dependent manner. To examine the physiological significance of Ran reduction, I first performed small interfering RNA(siRNA)-mediated abrogation of Ran in human diploid fibroblasts. Ran-depleted cells showed several senescent phenotypes. Furthermore, I found that nuclear accumulation of importinα, which was also observed in cells treated with siRNA against CAS, a specific export factor for importinα, occurred in the Ran-depleted cells before the cells showed senescent phenotypes. Further, the CAS-depleted cells also exhibited cellular senescence. Indeed, importinα gradually accumulated in a passage-dependent manner. Thus, reduction in Ran levels causes nuclear accumulation of importinα, leading to cellular senescence in normal cells. The amount of intracellular Ran may be critically related to cell senescence. The cellular aging process may proceed through gradual regression of Ran-dependent nucleocytoplasmic transport competency.