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PMID: 10749849 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/Cip1 promoter.

The Journal of biological chemistry ·Vol. 275 ·No. 24 ·2000-06-16 ·Pages 18391-8

Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS, Yang VW

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 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-like cis-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 antisense Gklf 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.

MeSH Terms
3T3 Cells Animals Cell Line Cyclin-Dependent Kinase Inhibitor p21 Cyclins/genetics DNA-Binding Proteins Growth Inhibitors/metabolism Kruppel-Like Factor 4 Kruppel-Like Transcription Factors Methyl Methanesulfonate/pharmacology Mice Polymerase Chain Reaction Promoter Regions, Genetic Rabbits Sp1 Transcription Factor/metabolism Transcription Factors/metabolism Transcriptional Activation Tumor Suppressor Protein p53/metabolism Zinc Fingers
Chemicals
Cdkn1a protein, mouse Cyclin-Dependent Kinase Inhibitor p21 Cyclins DNA-Binding Proteins Growth Inhibitors Klf4 protein, mouse Kruppel-Like Factor 4 Kruppel-Like Transcription Factors Sp1 Transcription Factor Transcription Factors Tumor Suppressor Protein p53 Methyl Methanesulfonate
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Zhang W
Departments of Medicine and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Geiman D E
Shields J M
Dang D T
Mahatan C S
Kaestner K H
Biggs J R
Kraft A S
Yang V W
References (65)
65 references, click to expand
  1. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
    Cell. 1993 Nov 19;75(4):805-16 PMID: 8242751
  2. WAF1, a potential mediator of p53 tumor suppression.
    Cell. 1993 Nov 19;75(4):817-25 PMID: 8242752
  3. p21 is a universal inhibitor of cyclin kinases.
    Nature. 1993 Dec 16;366(6456):701-4 PMID: 8259214
  4. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots.
    Genes Dev. 1993 Dec;7(12B):2556-64 PMID: 8276238
  5. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.
    Science. 1994 Jul 15;265(5170):346-55 PMID: 8023157
  6. Nuclear protein CBP is a coactivator for the transcription factor CREB.
    Nature. 1994 Jul 21;370(6486):223-6 PMID: 7913207
  7. Cell cycle control and cancer.
    Science. 1994 Dec 16;266(5192):1821-8 PMID: 7997877
  8. Inhibitors of mammalian G1 cyclin-dependent kinases.
    Genes Dev. 1995 May 15;9(10):1149-63 PMID: 7758941
  9. Viral oncoprotein binding to pRB, p107, p130, and p300.
    Virus Res. 1995 Feb;35(2):113-21 PMID: 7762286
  10. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage.
    Genes Dev. 1995 Apr 15;9(8):935-44 PMID: 7774811
  11. Essential role for p53-mediated transcription in E1A-induced apoptosis.
    Genes Dev. 1995 Sep 1;9(17):2184-92 PMID: 7657169
  12. Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter.
    J Biol Chem. 1995 Dec 1;270(48):28623-8 PMID: 7499379
  13. The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells.
    J Biol Chem. 1996 Jan 12;271(2):901-6 PMID: 8557703
  14. p53: puzzle and paradigm.
    Genes Dev. 1996 May 1;10(9):1054-72 PMID: 8654922
  15. Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest.
    J Biol Chem. 1996 Aug 16;271(33):20009-17 PMID: 8702718
  16. p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line.
    Exp Cell Res. 1996 Sep 15;227(2):171-81 PMID: 8831553
  17. A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells.
    J Biol Chem. 1996 Dec 6;271(49):31384-90 PMID: 8940147
  18. The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14106-11 PMID: 8943068
  19. p300 and CBP as transcriptional regulators and targets of oncogenic events.
    Biol Chem. 1996 Nov;377(11):685-8 PMID: 8960368
  20. Involvement of the Sp3 transcription factor in induction of p21Cip1/WAF1 in keratinocyte differentiation.
    J Biol Chem. 1997 Jan 10;272(2):1308-14 PMID: 8995437
  21. p53, the cellular gatekeeper for growth and division.
    Cell. 1997 Feb 7;88(3):323-31 PMID: 9039259
  22. Synergistic activation of transcription by CBP and p53.
    Nature. 1997 Jun 19;387(6635):819-23 PMID: 9194564
  23. Binding and modulation of p53 by p300/CBP coactivators.
    Nature. 1997 Jun 19;387(6635):823-7 PMID: 9194565
  24. The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation.
    Genes Dev. 1997 Jun 15;11(12):1583-95 PMID: 9203584
  25. Two potent nuclear localization signals in the gut-enriched Krüppel-like factor define a subfamily of closely related Krüppel proteins.
    J Biol Chem. 1997 Jul 18;272(29):18504-7 PMID: 9218496
  26. Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line.
    J Biol Chem. 1997 Aug 29;272(35):22199-206 PMID: 9268365
  27. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1.
    Nature. 1997 Sep 11;389(6647):187-90 PMID: 9296497
  28. Chromatin remodeling and the control of gene expression.
    J Biol Chem. 1997 Nov 7;272(45):28171-4 PMID: 9353261
  29. Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites.
    Biochem Biophys Res Commun. 1997 Dec 8;241(1):142-50 PMID: 9405248
  30. The p53 network.
    J Biol Chem. 1998 Jan 2;273(1):1-4 PMID: 9417035
  31. Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains.
    J Biol Chem. 1998 Jan 9;273(2):1026-31 PMID: 9422764
  32. Expression of the gut-enriched Krüppel-like factor gene during development and intestinal tumorigenesis.
    FEBS Lett. 1997 Dec 15;419(2-3):239-43 PMID: 9428642
  33. Identification of the DNA sequence that interacts with the gut-enriched Krüppel-like factor.
    Nucleic Acids Res. 1998 Feb 1;26(3):796-802 PMID: 9443972
  34. Factors associated with the mammalian RNA polymerase II holoenzyme.
    Nucleic Acids Res. 1998 Feb 1;26(3):847-53 PMID: 9443979
  35. Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells.
    J Biol Chem. 1998 Apr 24;273(17):10618-23 PMID: 9553123
  36. Progesterone regulates transcription of the p21(WAF1) cyclin- dependent kinase inhibitor gene through Sp1 and CBP/p300.
    J Biol Chem. 1998 Apr 24;273(17):10696-701 PMID: 9553133
  37. Transactivation of the human keratin 4 and Epstein-Barr virus ED-L2 promoters by gut-enriched Krüppel-like factor.
    J Biol Chem. 1998 Apr 24;273(17):10747-54 PMID: 9553140
  38. Tumor suppressor p53 can participate in transcriptional induction of the GADD45 promoter in the absence of direct DNA binding.
    Mol Cell Biol. 1998 May;18(5):2768-78 PMID: 9566896
  39. BRCA1 physically associates with p53 and stimulates its transcriptional activity.
    Oncogene. 1998 Apr 2;16(13):1713-21 PMID: 9582019
  40. Sp1, but not Sp3, functions to mediate promoter activation by TGF-beta through canonical Sp1 binding sites.
    Nucleic Acids Res. 1998 May 15;26(10):2449-56 PMID: 9580699
  41. Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members.
    Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6733-8 PMID: 9618481
  42. The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion.
    J Biol Chem. 1998 Jul 10;273(28):17917-25 PMID: 9651398
  43. The complexity of p53 modulation: emerging patterns from divergent signals.
    Genes Dev. 1998 Oct 1;12(19):2973-83 PMID: 9765199
  44. Signaling to p53: breaking the MDM2-p53 circuit.
    Cell. 1998 Oct 2;95(1):5-8 PMID: 9778240
  45. Transcriptional regulation of the p21((WAF1/CIP1)) gene.
    Exp Cell Res. 1999 Feb 1;246(2):280-9 PMID: 9925742
  46. Regulation of p53 downstream genes.
    Semin Cancer Biol. 1998;8(5):345-57 PMID: 10101800
  47. GKLF in thymus epithelium as a developmentally regulated element of thymocyte-stroma cross-talk.
    Mech Dev. 1999 Mar;81(1-2):103-13 PMID: 10330488
  48. Growth arrest of melanoma cells is differentially regulated by contact inhibition and serum deprivation.
    DNA Cell Biol. 1999 May;18(5):357-67 PMID: 10360837
  49. Mammalian Krüppel-like transcription factors: more than just a pretty finger.
    Trends Biochem Sci. 1999 Jun;24(6):236-40 PMID: 10366853
  50. Klf4 is a transcription factor required for establishing the barrier function of the skin.
    Nat Genet. 1999 Aug;22(4):356-60 PMID: 10431239
  51. p21(WAF1/CIP1) is upregulated by the geranylgeranyltransferase I inhibitor GGTI-298 through a transforming growth factor beta- and Sp1-responsive element: involvement of the small GTPase rhoA.
    Mol Cell Biol. 1998 Dec;18(12):6962-70 PMID: 9819384
  52. Characterization of the structure and regulation of the murine gene encoding gut-enriched Krüppel-like factor (Krüppel-like factor 4).
    Nucleic Acids Res. 1999 Dec 1;27(23):4562-9 PMID: 10556311
  53. Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects.
    J Biol Chem. 1999 Dec 3;274(49):34940-7 PMID: 10574969
  54. Histone acetyltransferase complexes and their link to transcription.
    Crit Rev Eukaryot Gene Expr. 1999;9(3-4):231-43 PMID: 10651240
  55. Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction.
    Nucleic Acids Res. 2000 Mar 1;28(5):1106-13 PMID: 10666450
  56. Immunohistology of the antigenic pattern of a continuous cell line from a human colon tumor.
    J Natl Cancer Inst. 1975 Sep;55(3):555-60 PMID: 1159834
  57. DNA damage-inducible transcripts in mammalian cells.
    Proc Natl Acad Sci U S A. 1988 Dec;85(23):8800-4 PMID: 3194391
  58. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents.
    Mol Cell Biol. 1989 Oct;9(10):4196-203 PMID: 2573827
  59. Suppression of human colorectal carcinoma cell growth by wild-type p53.
    Science. 1990 Aug 24;249(4971):912-5 PMID: 2144057
  60. Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence.
    Science. 1990 Nov 30;250(4985):1259-62 PMID: 2244209
  61. p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts.
    Genes Dev. 1991 Dec;5(12B):2375-85 PMID: 1752433
  62. p300, and p300-associated proteins, are components of TATA-binding protein (TBP) complexes.
    Oncogene. 1993 Jun;8(6):1639-47 PMID: 8502484
  63. The p53-mdm-2 autoregulatory feedback loop.
    Genes Dev. 1993 Jul;7(7A):1126-32 PMID: 8319905
  64. Phosphorylated CREB binds specifically to the nuclear protein CBP.
    Nature. 1993 Oct 28;365(6449):855-9 PMID: 8413673
  65. Analysis of the mammalian gadd45 gene and its response to DNA damage.
    J Biol Chem. 1993 Nov 15;268(32):24385-93 PMID: 8226988
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.C000062200
Published
2000-06-16
Pages
18391-8
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2231805
Subset
IM
Grants
NCI NIH HHS · R01 CA084197 · United States
NCI NIH HHS · R01 CA084197-01 · United States
NCI NIH HHS · R01 CA084197-09 · United States
External Links
PubMed source DOI: 10.1074/jbc.C000062200 PMC Full Text View journal details
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