Transcription factor Sp1 prevents TRF2(Delta B Delta M)-induced premature senescence in human diploid fibroblasts

Abstract

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(Delta B Delta M)-induced senescence model in human diploid fibroblasts. We observed that the expression of Sp1 is down-regulated in the TRF2(Delta B Delta M)-induced senescence, which was mediated by ATM and p38 MAPK. In addition, overexpression of Sp1 prevented the TRF2(Delta B Delta M)-induced senescence. Among transcriptional targets of Sp1, expression levels of nuclear transport genes such as karyopherin alpha, Nup107, and Nup50 were down-regulated in the TRF2(Delta B Delta M)-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.