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 Kraft, Vincent W. Yang

Research output: Contribution to journalArticle

261 Citations (Scopus)

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

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Methyl Methanesulfonate
DNA Damage
Chemical activation
Cyclin-Dependent Kinase Inhibitor p21
Gene encoding
Trans-Activators
Antisense Oligonucleotides
Genomic Instability
DNA
Cell Cycle Checkpoints
Oligonucleotides
Genes
Tumors
Cells
Messenger RNA
Serum
Neoplasms
GKLF protein

ASJC Scopus subject areas

  • Biochemistry

Cite this

Zhang, W., Geiman, D. E., Shields, J. M., Dang, D. T., Mahatan, C. S., Kaestner, K. H., ... 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

The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21(WAF1)/(Cip)1 promoter. / Zhang, Weiqing; Geiman, Deborah E.; Shields, Janiel M.; Dang, Duyen T.; Mahatan, Channing S.; Kaestner, Klaus H.; Biggs, Joseph R.; Kraft, Andrew; Yang, Vincent W.

In: Journal of Biological Chemistry, Vol. 275, No. 24, 16.06.2000, p. 18391-18398.

Research output: Contribution to journalArticle

Zhang, Weiqing ; Geiman, Deborah E. ; Shields, Janiel M. ; Dang, Duyen T. ; Mahatan, Channing S. ; Kaestner, Klaus H. ; Biggs, Joseph R. ; Kraft, Andrew ; Yang, Vincent W. / The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21(WAF1)/(Cip)1 promoter. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 24. pp. 18391-18398.
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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.",
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AU - Geiman, Deborah E.

AU - Shields, Janiel M.

AU - Dang, Duyen T.

AU - Mahatan, Channing S.

AU - Kaestner, Klaus H.

AU - Biggs, Joseph R.

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AB - 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.

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