The transcription factor S p1 is responsible for aging‐dependent altered nucleocytoplasmic trafficking

Summary Hyporesponsiveness to external signals, such as growth factors and apoptotic stimuli, is a cardinal feature of cellular senescence. We previously reported that an aging‐dependent marked reduction in nucleocytoplasmic trafficking ( NCT )‐related genes could be responsible for this phenomenon. In searching for the mechanism, we identified the transcription factor, S p1, as a common regulator of NCT genes, including various nucleoporins, importins, exportins, and R an GTP ase cycle‐related genes. Sp1 knockdown led to a reduction of those genes in young human diploid fibroblast cells ( HDF ); S p1 overexpression induced those genes in senescent cells. In addition, epidermal growth factor stimulation–induced p‐ ERK 1/2 nuclear translocation and E lk‐1 phosphorylation were severely impaired by S p1 depletion in young HDF s; S p1 overexpression restored the nuclear translocation of p‐ ERK 1/2 in senescent HDF s. Furthermore, we observed that S p1 protein levels were decreased in senescent cells, and H 2 O 2 treatment decreased S p1 levels in a proteasome‐dependent manner. In addition, O ‐ G lc NA cylation of S p1 was decreased in senescent cells as well as in H 2 O 2 ‐treated cells. Taken together, these results suggest that S p1 could be a key regulator in the control of NCT genes and that reactive oxygen species‐mediated alteration in S p1 stability may be responsible for the generalized repression of those genes, leading to formation of the senescence‐dependent functional nuclear barrier, resulting in subsequent hyporesponsiveness to external signals.