The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21(WAF1)/(Cip)1 promoter

Weiqing Zhang, Deborah E. Geiman, Janiel M. Shields, Duyen T. Dang, Channing S. Mahatan, Klaus H. Kaestner, Joseph R. Biggs, Andrew S. Kraft, Vincent W. Yang

Research output: Contribution to journalArticle

264 Scopus citations

Abstract

An important mechanism by which the tumor suppressor p53 maintains genomic stability is to induce cell cycle arrest through activation of the cyclin-dependent kinase inhibitor p21(WAF1)/(Cip1) gene. We show that the gene encoding the gut-enriched Kruppel-like factor (GKLF, KLF4) is concurrently induced with p21(WAF1)/(Cip1) during serum deprivation and DNA damage elicited by methyl methanesulfonate. The increases in expression of both Gklf and p21(WAF1)/(Cip1) due to DNA damage are dependent on p53. Moreover, during the first 30 min of methyl methanesulfonate treatment, the rise in Gklf mRNA level precedes that in p21(WAF1/Cip1), suggesting that GKLF may be involved in the induction of p21(WAF1)/(Cap1). Indeed, GKLF activates p21(WAF1)/(Cip1) through a specific Sp1-like cis-element in the p21(WAF1)/(Cip)1 proximal promoter. The same element is also required by p53 to activate the p21(WAF1)/(Cip)1 promoter, although p53 does not bind to it. Potential mechanisms by which p53 activates the p21(WAF1)/(CAip)1 promoter include a physical interaction between p53 and GKLF and the transcriptional induction of Gklf by p53. Consequently, the two transactivators cause a synergistic induction of the p21(WAF1)/(Cip)1 promoter activity. The physiological relevance of GKLF in mediating p53-dependent induction of p21(WAF)(1)/(Cip)1 is demonstrated by the ability of antisense Gklf oligonucleotides to block the production of p21(WAF1)/(Cip)1 in response to p53 activation. These findings suggest that GKLF is an essential mediator of p53 in the transcriptional induction of p21(WAF1)/(Cip)1 and may be part of a novel pathway by which cellular responses to stress are modulated.

Original languageEnglish (US)
Pages (from-to)18391-18398
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number24
DOIs
StatePublished - Jun 16 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhang, W., Geiman, D. E., Shields, J. M., Dang, D. T., Mahatan, C. S., Kaestner, K. H., Biggs, J. R., Kraft, A. S., & Yang, V. W. (2000). The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21(WAF1)/(Cip)1 promoter. Journal of Biological Chemistry, 275(24), 18391-18398. https://doi.org/10.1074/jbc.C000062200