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The transcription factor Sp1 is responsible for aging‐dependent altered nucleocytoplasmic trafficking

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, Sp1, as a common regulator of NCT genes, including various nucleoporins, importins, exportins, and Ran GTPase cycle‐related genes. Sp1 knockdown led to a reduction of those genes in young human diploid fibroblast cells (HDF); Sp1 overexpression induced those genes in senescent cells. In addition, epidermal growth factor stimulation–induced p‐ERK1/2 nuclear translocation and Elk‐1 phosphorylation were severely impaired by Sp1 depletion in young HDFs; Sp1 overexpression restored the nuclear translocation of p‐ERK1/2 in senescent HDFs. Furthermore, we observed that Sp1 protein levels were decreased in senescent cells, and H2O2 treatment decreased Sp1 levels in a proteasome‐dependent manner. In addition, O‐GlcNAcylation of Sp1 was decreased in senescent cells as well as in H2O2‐treated cells. Taken together, these results suggest that Sp1 could be a key regulator in the control of NCT genes and that reactive oxygen species‐mediated alteration in Sp1 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.