Transcriptional activation of p21WAF1/CIP1 is mediated by increased DNA binding activity and increased interaction between p53 and Sp1 via phosphorylation during replicative senescence of human embryonic fibroblasts

Hyun Seok Kim, Jee In Heo, Seong Hoon Park, Jong Yeon Shin, Hong Jun Kang, Min Ju Kim, Sung Chan Kim, Jaebong Kim, Jae Bong Park, Jae Yong Lee

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Although p21WAF1/CIP1 is known to be elevated during replicative senescence of human embryonic fibroblasts (HEFs), the mechanism for p21 up-regulation has not been elucidated clearly. In order to explore the mechanism, we analyzed expression of p21 mRNA and protein and luciferase activity of full-length p21 promoter. The result demonstrated that p21 up-regulation was accomplished largely at transcription level. The promoter assay using serially-deleted p21 promoter constructs revealed that p53 binding site was the most important site and Sp1 binding sites were necessary but not sufficient for transcriptional activation of p21. In addition, p53 protein was shown to interact with Sp1 protein. The interaction was increased in aged fibroblasts and was regulated by phosphorylation of p53 and Sp1. DNA binding activity of p53 was significantly elevated in aged fibroblasts but that of Sp1 was not. DNA binding activities of p53 and Sp1 were also regulated by phosphorylation. Phosphorylation of p53 at serine-15 and of Sp1 at serines appears to be involved. Taken together, the result demonstrated that p21 transcription during replicative senescence of HEFs is up-regulated by increase in DNA binding activity and interaction between p53 and Sp1 via phosphorylation.

Original languageEnglish
Pages (from-to)2397-2408
Number of pages12
JournalMolecular Biology Reports
Volume41
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • Senescence
  • Sp1
  • p21
  • p53

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