An Hyun Ju, Lee Hyeon Ju, Jang Suhwa, Jung Yu-Jin, Choi Sun Shim, Park Sang Chul, Han Jeong A
Department of Biochemistry and Molecular Biology, Kangwon National University School of Medicine, Chuncheon, 200-701, South Korea.
Department of Biomedical Science, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, 133-791, South Korea.
Mol Cell Biochem. 2016 Mar;414(1-2):201-8. doi: 10.1007/s11010-016-2672-7. Epub 2016 Feb 23.
Telomere uncapping is thought to be the fundamental cause of replicative cellular senescence, but the cellular machineries mediating this process have not been fully understood. In the present study, we present the role of Sp1 transcription factor in the state of telomere uncapping using the TRF2(ΔBΔM)-induced senescence model in human diploid fibroblasts. We observed that the expression of Sp1 is down-regulated in the TRF2(ΔBΔM)-induced senescence, which was mediated by ATM and p38 MAPK. In addition, overexpression of Sp1 prevented the TRF2(ΔBΔM)-induced senescence. Among transcriptional targets of Sp1, expression levels of nuclear transport genes such as karyopherin α, Nup107, and Nup50 were down-regulated in the TRF2(ΔBΔM)-induced senescence, which was prevented by Sp1 overexpression. Moreover, inhibition of the nuclear transport by wheat germ agglutinin (an import inhibitor) and leptomycin B (an export inhibitor) induced premature senescence. These results suggest that Sp1 is an anti-senescence transcription factor in the telomere uncapping-induced senescence and that down-regulation of Sp1 leads to the senescence via down-regulation of the nuclear transport.
端粒解帽被认为是细胞复制性衰老的根本原因，但介导这一过程的细胞机制尚未完全明确。在本研究中，我们利用人二倍体成纤维细胞中TRF2(ΔBΔM)诱导的衰老模型，阐述了Sp1转录因子在端粒解帽状态中的作用。我们观察到，在TRF2(ΔBΔM)诱导的衰老过程中，Sp1的表达下调，这一过程由ATM和p38丝裂原活化蛋白激酶介导。此外，Sp1的过表达可阻止TRF2(ΔBΔM)诱导的衰老。在Sp1的转录靶点中，核转运基因如核转运蛋白α、核孔蛋白107和核孔蛋白50的表达水平在TRF2(ΔBΔM)诱导的衰老过程中下调，而Sp1的过表达可阻止这种下调。此外，麦胚凝集素（一种输入抑制剂）和 leptomycin B（一种输出抑制剂）对核转运的抑制可诱导细胞早衰。这些结果表明，Sp1是端粒解帽诱导衰老过程中的一种抗衰老转录因子，Sp1的下调通过核转运的下调导致细胞衰老。
