• Open Access

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

Authors

  • Sung Y. Kim,

    1. Department of Biochemistry, Gachon University of Medicine and Science, Incheon, South Korea
    2. Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea
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  • Hyun T. Kang,

    1. Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea
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  • Jeong A. Han,

    1. Department of Biochemistry and Molecular Biology, School of Medicine, Kangwon National University, Chuncheon, South Korea
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  • Sang C. Park

    Corresponding author
    1. Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea
    • Department of Biochemistry, Gachon University of Medicine and Science, Incheon, South Korea
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Correspondence

Sang Chul Park, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Getpearl Ro, Songdo Dong, Yeonsoo Ku, Incheon 406-840, South Korea. Tel.: +82 32 899 6025; fax: +82 32 899 6029; e-mail: blueocean@gachon.ac.kr

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, 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.

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