The Gut-enriched Krüppel-like Factor (Krüppel-like Factor 4) Mediates the Transactivating Effect of p53 on the p21 WAF1/Cip1 Promoter

• Published in: The Journal of biological chemistry Vol. 275; no. 24; pp. 18391 - 18398
• Main Authors: Zhang, Weiqing, Geiman, Deborah E., Shields, Janiel M., Dang, Duyen T., Mahatan, Channing S., Kaestner, Klaus H., Biggs, Joseph R., Kraft, Andrew S., Yang, Vincent W.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.06.2000
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C000062200

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 Krüppel-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/Cip1. Indeed, GKLF activates p21 WAF1/Cip1 through a specific Sp1-likecis-element in the p21 WAF1/Cip1 proximal promoter. The same element is also required by p53 to activate the p21 WAF1/Cip1 promoter, although p53 does not bind to it. Potential mechanisms by which p53 activates the p21 WAF1/Cip1 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/Cip1 promoter activity. The physiological relevance of GKLF in mediating p53-dependent induction of p21 WAF1/Cip1 is demonstrated by the ability of antisenseGklf oligonucleotides to block the production of p21 WAF1/Cip1 in response to p53 activation. These findings suggest that GKLF is an essential mediator of p53 in the transcriptional induction of p21 WAF1/Cip1 and may be part of a novel pathway by which cellular responses to stress are modulated.