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

• Published in: The Journal of biological chemistry 2000-06, Vol.275 (24), p.18391-18398
• Main Authors: Zhang, W, Geiman, DE, Shields, J M, Dang, D T, Mahatan, C S, Kaestner, KH, Biggs, J R, Kraft, A S, Yang, V W
• Format: Article
• Language: English
• Subjects: Cip1 gene; GKLF protein; KLF4 protein; Krueppel-like factor 4; p21 protein; WAF1 gene
• 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 super(WAF1/Cip1) gene. We show that the gene encoding the gut-enriched Krueppel-like factor (GKLF, KLF4) is concurrently induced with p21 super(WAF1/Cip1) during serum deprivation and DNA damage elicited by methyl methanesulfonate. The increases in expression of both Gklf and p21 super(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 super(WAF1/Cip1), suggesting that GKLF may be involved in the induction of p21 super(WAF1/Cip1). Indeed, GKLF activates p21 super(WAF1/Cip1) through a specific Sp1-like cis-element in the p21 super(WAF1/Cip1) proximal promoter. The same element is also required by p53 to activate the p21 super(WAF1/Cip1) promoter, although p53 does not bind to it. Potential mechanisms by which p53 activates the p21 super(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 super(WAF1/Cip1) promoter activity. The physiological relevance of GKLF in mediating p53-dependent induction of p21 super(WAF1/Cip1) is demonstrated by the ability of antisense Gklf oligonucleotides to block the production of p21 super(WAF1/Cip1) in response to p53 activation. These findings suggest that GKLF is an essential mediator of p53 in the transcriptional induction of p21 super(WAF1/Cip1) and may be part of a novel pathway by which cellular responses to stress are modulated.