Written | 2008-10 | Amr M Ghaleb, Vincent W Yang |
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine Atlanta, Georgia, USA |
Identity |
Alias (NCBI) | GKLF | EZF |
HGNC (Hugo) | KLF4 |
HGNC Alias symb | EZF | GKLF |
HGNC Alias name | gut Kruppel-like factor |
HGNC Previous name | Kruppel-like factor 4 (gut) |
LocusID (NCBI) | 9314 |
Atlas_Id | 44316 |
Location | 9q31.2 [Link to chromosome band 9q31] |
Location_base_pair | Starts at 107484852 and ends at 107489769 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping KLF4.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
H1F0 (22q13.1) / KLF4 (9q31.2) | SCAMP5 (15q24.2) / KLF4 (9q31.2) |
DNA/RNA |
![]() | |
The structure of the murine KLF4 gene. The four exons of the murine GKLF gene are identified by Roman numerals. The translated region or open reading frame is depicted in black. The locations of restriction sites for several endonucleases are labeled: Nc, NcoI; N, NotI; K, KpnI; H, HindIII; Xh, XhoI; Sm, SmaI; Xb, XbaI; Bg, BglII; B, BamHI. | |
Description | A full-length mouse cDNA clone encoding KLF4 was initially isolated from a NIH3T3 cDNA library by reduced stringency screening with a DNA probe containing the zinc finger region of an immediate early gene product, Zif268 or Egr1. A distinct feature of the KLF4 gene is the highly GC-rich nature of the sequence near its 5'-end. Thus, the G+C content of the 1000 nt 5'-flanking region is 67% and that of the 5'-untranslated region is 63%. Moreover, the bulk of the GC residues are concentrated in the region between nt -600 and +300 of the gene where the G+C content is 82%. The gene has four exons, each containing a portion of the translated region. |
Transcription | The open-reading frame of the Klf4 gene encodes a polypeptide of 483 amino acids with a predicted molecular weight of 53 kDa. The entire polypeptide sequence of Klf4 with the exception of the first amino acid is encoded by exons 2, 3 and 4. |
Protein |
Description | KLF4 encodes a polypeptide of 483 aa and similar to KLFs, contains three Kruppel-type zinc fingers in the very C-terminal end. The region immediately N terminal to the three zinc fingers is a 20-aa peptide containing a cluster of basic aa residues, which is essential for the nuclear localization of the protein. |
Expression | KLF4 is a nuclear protein whose cellular address depends on two nuclear localization signals. Expression of the KLF4 gene is developmentally regulated, with a higher level of expression occurring toward the later stage of fetal development. In adults, KLF4 is highly enriched in epithelial tissues, including the skin, lung, and intestine. In the intestinal tract, KLF4 is predominantly present in the terminally differentiated, postmitotic epithelial cells lining the villus border of the small intestine and the upper crypt region of the large intestine. In cultured cells, the level of KLF4 mRNA is associated with the growth-arrested state in a manner similar to that observed in the intestinal epithelium. Expression of KLF4 can also be found in a select number of other organs including the lung, testis, skin and thymus, and in vascular endothelial cells. |
![]() | |
Localisation | KLF4 is a nuclear protein that contains two potent nuclear localization signals (NLSs), one within the three zinc fingers and the other in a cluster of basic amino acids immediately adjacent to the first zinc finger. These two NLSs define a subfamily of three closely related KLFs: KLF1, KLF2, and KLF4. |
Function | KLF4 binds to DNA sequence elements that are GC-rich. A consensus DNA binding sequence was empirically determined and is present in the promoters of many genes, including the CACCC element and the basic transcription element (BTE). KLF4 inhibits the promoter of the cytochrome P-450IA1 ( CYP1A1 ) gene in a BTE-dependent manner. In cultured cells, the level of KLF4 mRNA is associated with the growth-arrested state in a manner similar to that observed in the intestinal epithelium. Forced expression of KLF4 in cultured cells results in the inhibition of DNA synthesis. The induction of KLF4 is also correlated with an increase in the level of p21WAF1/CIP1, a critical checkpoint protein that inhibits cell cycle progression and is essential in mediating the cell cycle arrest at both the G1/S and G2/M boundaries. Importantly, KLF4 is essential in the induction of expression of the p21WAF1/CIP1 gene in response to DNA damage by binding to a specific cis-DNA element in the p21WAF1/CIP1 proximal promoter to activate p21WAF1/CIP1 expression. cDNA microarray analysis of the transcriptional profiles of KLF4 demonstrates that KLF4 inhibits the cell cycle by coordinately regulating expression of numerous cell cycle regulatory genes. KLF4 mediates the cell cycle checkpoint function of the tumor suppressor p53 suggesting that it may itself act as a tumor suppressor. Its mRNA are reduced in intestinal adenomas of ApcMin/+ mice and colonic adenomas of patients with familial adenomatous polyposis (FAP) when compared with surrounding normal tissues. Conversely, overexpression of KLF4 in the human colon cancer cell line RKO, which does not express endogenous KLF4, results in reduced tumorigenesis in vitro and in vivo. KLF4 plays a role in mediating the tumor-suppressive function of APC. KLF4 can down-regulate the level of beta-catenin and can bind directly to the transcriptional activation domain of beta-catenin to inhibit beta-catenin-mediated transcription. KLF4 haploinsufficiency in ApcMin/+ mice lead to significantly more intestinal adenomas than ApcMin/+ mice alone. In vivo, KLF4 is required for goblet cell differentiation in the intestine and eye conjuctiva. KLF4 has been shown to be down-regulated by Notch pathway and is important in maintaining the normal skin barrier. Induction of KLF4 significantly reduces the percentage of apoptotic cells following g-irradiation. Upregulation of KLF4 also inhibits expression of the gene encoding the pro-apoptotic protein Bax following DNA damage. Taken together, these studies place KLF4 in an interesting and important position between the Wnt and Notch signaling pathways, both of which are crucial for intestinal tumorigenesis. Additional studies are likely to further reveal the exact mechanism by which KLF4 mediates the crosstalk functions of these two key pathways in CRC. |
![]() | |
Homology | KLF4 belongs to the SP1 / KLF transcription factor family that is highly conserved among species (from Drosophila to human). Mouse KLF4 and is 90% identical to human KLF4. The carboxyl terminus of KLF4 contains three C2H2-zinc fingers that are most closely related to another member of the family, KLF2. |
Mutations |
Note | A number of colon cancer cell lines contain point mutations in the coding region of KLF4 that resulted in a diminished ability to activate the p21WAF1/Cip1 promoter. Also there is evidence for LOH of the KLF4 locus and of hypermethylation of the 5'-UTR in resected CRC specimens and colon cancer cell lines. |
Implicated in |
Note | |
Entity | Colorectal Cancer (CRC) |
Disease | The relevance of KLF4 in the pathogenesis of human CRC is demonstrated by a significant reduction of KLF4 mRNA levels in colorectal adenoma and adenocarcinoma compared with matched normal colonic tissues. There is also evidence for LOH in a subset of CRC and in a panel of CRC cell lines. Moreover, the 5-untranslated region of the KLF4 gene is found to be hypermethylated in a subset of CRC. Lastly, several point mutations are identified in KLF4 that result in a diminished ability to activate the p21WAF1/CIP1 promoter in some of the CRC cell lines. These studies suggest that KLF4 is a tumor suppressor, at least in a fraction of patients with CRC. Recent studies demonstrating that KLF4 is involved in maintaining centrosome duplication and thus genomic stability further illustrate the mechanism by which KLF4 may be involved in tumor suppression. |
Entity | Goblet cells hypoplasia. |
Disease | Mice homozygous for a null mutation in the Klf4 gene die shortly after birth, for unknown reasons. Immediately following birth, Klf4-/- mice have a 90% reduction in the number of goblet cells in their colon, show abnormal expression of the goblet cell-specific marker Muc2, and have abnormal goblet cell morphology. |
Entity | Gastric cancer |
Disease | Mutational analysis indicates that the KLF4 gene is subject to deletion, mutation and methylation silencing in a significant proportion of colon and gastric cancers. Conditional Klf4-knockout mouse specific for the gastric epithelium, loss of Klf4 results in increased proliferation and differentiation in the stomach, culminating in precancerous changes altered. |
Entity | Breast cancer |
Disease | KLF4 levels are elevated in up to 70% of mammary carcinomas. |
Prognosis | Nuclear localization of KLF4 is associated with an aggressive phenotype in early stage breast cancer. |
Oncogenesis | Oncogene. |
Entity | Dysplastic oral squamous-cell carcinomas |
Disease | KLF4 levels are elevated in oropharyngial dysplastic squamous-cell carcinomas. |
Entity | Squamous cell carcinoma |
Disease | Ectopic expression of KLF4 in basal keratinocytes of transgenic mice results in dysplastic lesions that resemble squamous cell carcinoma in situ. |
Bibliography |
Kruppel-like factor 4 (gut-enriched Kruppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. |
Chen X, Johns DC, Geiman DE, Marban E, Dang DT, Hamlin G, Sun R, Yang VW. |
J Biol Chem. 2001 Aug 10;276(32):30423-8. Epub 2001 Jun 4. |
PMID 11390382 |
Transcriptional profiling of Kruppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. |
Chen X, Whitney EM, Gao SY, Yang VW. |
J Mol Biol. 2003 Feb 21;326(3):665-77. |
PMID 12581631 |
A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with 'zinc finger' sequences. |
Christy BA, Lau LF, Nathans D. |
Proc Natl Acad Sci U S A. 1988 Nov;85(21):7857-61. |
PMID 3141919 |
Decreased expression of the gut-enriched Kruppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients. |
Dang DT, Bachman KE, Mahatan CS, Dang LH, Giardiello FM, Yang VW. |
FEBS Lett. 2000 Jul 7;476(3):203-7. |
PMID 10913614 |
Overexpression of Kruppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity. |
Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW. |
Oncogene. 2003 May 29;22(22):3424-30. |
PMID 12776194 |
The biology of the mammalian Kruppel-like family of transcription factors. |
Dang DT, Pevsner J, Yang VW. |
Int J Biochem Cell Biol. 2000 Nov-Dec;32(11-12):1103-21. (REVIEW) |
PMID 11137451 |
Increase of GKLF messenger RNA and protein expression during progression of breast cancer. |
Foster KW, Frost AR, McKie-Bell P, Lin CY, Engler JA, Grizzle WE, Ruppert JM. |
Cancer Res. 2000 Nov 15;60(22):6488-95. |
PMID 11103818 |
Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. |
Foster KW, Liu Z, Nail CD, Li X, Fitzgerald TJ, Bailey SK, Frost AR, Louro ID, Townes TM, Paterson AJ, Kudlow JE, Lobo-Ruppert SM, Ruppert JM. |
Oncogene. 2005 Feb 24;24(9):1491-500. |
PMID 15674344 |
A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. |
Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B. |
J Biol Chem. 1996 Dec 6;271(49):31384-90. |
PMID 8940147 |
Kruppel-like factor 4 exhibits anti-apoptotic activity following gamma-radiation-induced DNA damage. |
Ghaleb AM, Katz JP, Kaestner KH, Du JX, Yang VW. |
Oncogene. 2007 Apr 5;26(16):2365-73. Epub 2006 Oct 2. |
PMID 17016435 |
Haploinsufficiency of Kruppel-Like Factor 4 Promotes Adenomatous Polyposis Coli-Dependent Intestinal Tumorigenesis. |
Ghaleb AM, McConnell BB, Nandan MO, Katz JP, Kaestner KH, Yang VW. |
Cancer Res. 2007 Aug 1;67(15):7147-54. |
PMID 17671182 |
Kruppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation. |
Ghaleb AM, Nandan MO, Chanchevalap S, Dalton WB, Hisamuddin IM, Yang VW. |
Cell Res. 2005 Feb;15(2):92-6. (REVIEW) |
PMID 15740636 |
The Pathobiology of Kruppel-like Factors in Colorectal Cancer. |
Ghaleb AM, Yang VW. |
Curr Colorectal Cancer Rep. 2008 Apr;4(2):59-64. (REVIEW) |
PMID 18504508 |
Transactivation of the human keratin 4 and Epstein-Barr virus ED-L2 promoters by gut-enriched Kruppel-like factor. |
Jenkins TD, Opitz OG, Okano J, Rustgi AK. |
J Biol Chem. 1998 Apr 24;273(17):10747-54. |
PMID 9553140 |
The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. |
Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW, Kaestner KH. |
Development. 2002 Jun;129(11):2619-28. |
PMID 12015290 |
A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. |
Koritschoner NP, Bocco JL, Panzetta-Dutari GM, Dumur CI, Flury A, Patrito LC. |
J Biol Chem. 1997 Apr 4;272(14):9573-80. |
PMID 9083102 |
Characterization of the structure and regulation of the murine gene encoding gut-enriched Kruppel-like factor (Kruppel-like factor 4). |
Mahatan CS, Kaestner KH, Geiman DE, Yang VW. |
Nucleic Acids Res. 1999 Dec 1;27(23):4562-9. |
PMID 10556311 |
The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology. |
McConnell BB, Ghaleb AM, Nandan MO, Vincent W. Yang. |
Bioessays. 2007 Jun;29(6):549-57. (REVIEW) |
PMID 17508399 |
Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. |
Pandya AY, Talley LI, Frost AR, Fitzgerald TJ, Trivedi V, Chakravarthy M, Chhieng DC, Grizzle WE, Engler JA, Krontiras H, Bland KI, LoBuglio AF, Lobo-Ruppert SM, Ruppert JM. |
Clin Cancer Res. 2004 Apr 15;10(8):2709-19. |
PMID 15102675 |
GKLF in thymus epithelium as a developmentally regulated element of thymocyte-stroma cross-talk. |
Panigada M, Porcellini S, Sutti F. |
Mech Dev. 1999 Mar;81(1-2):103-13. |
PMID 10330488 |
The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a contextdependent oncogene. |
Rowland BD, Bernards R, Peeper DS. |
Nat Cell Biol. 2005 Nov;7(11):1074-82. |
PMID 16244670 |
A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Kruppel, a Drosophila segmentation gene. |
Schuh R, Aicher W, Gaul U, Cote S, Preiss A, Maier D, Seifert E, Nauber U, Schroder C, Kemler R, et al. |
Cell. 1986 Dec 26;47(6):1025-32. |
PMID 3096579 |
Klf4 is a transcription factor required for establishing the barrier function of the skin. |
Segre JA, Christoph Bauer C, Fuchs E. |
Nat Genet. 1999 Aug;22(4):356-60. |
PMID 10431239 |
Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation. |
Shie JL, Chen ZY, O'Brien MJ, Pestell RG, Lee ME, Tseng CC. |
Am J Physiol Gastrointest Liver Physiol. 2000 Oct;279(4):G806-14. |
PMID 11005769 |
Identification of the DNA sequence that interacts with the gut-enriched Kruppel-like factor. |
Shields JM, Yang VW. |
Nucleic Acids Res. 1998 Feb 1;26(3):796-802. |
PMID 9443972 |
cDNA cloning and transcriptional properties of a novel GC box-binding protein, BTEB2. |
Sogawa K, Imataka H, Yamasaki Y, Kusume H, Abe H, Fujii-Kuriyama Y. |
Nucleic Acids Res. 1993 Apr 11;21(7):1527-32. |
PMID 8479902 |
Expression of the gut-enriched Kruppel-like factor gene during development and intestinal tumorigenesis. |
Ton-That H, Kaestner KH, Shields JM, Mahatanankoon CS, Yang VW. |
FEBS Lett. 1997 Dec 15;419(2-3):239-43. |
PMID 9428642 |
Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression. |
Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, Wu TT, Huang S, Xie K. |
Cancer Res. 2005 Apr 1;65(7):2746-54. |
PMID 15805274 |
Human EZF, a Kruppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. |
Yet SF, McA'Nulty MM, Folta SC, Yen HW, Yoshizumi M, Hsieh CM, Layne MD, Chin MT, Wang H, Perrella MA, Jain MK, Lee ME. |
J Biol Chem. 1998 Jan 9;273(2):1026-31. |
PMID 9422764 |
Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. |
Yoon HS, Chen X, Yang VW. |
J Biol Chem. 2003 Jan 24;278(4):2101-5. Epub 2002 Nov 8. |
PMID 12427745 |
Kruppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage. |
Yoon HS, Ghaleb AM, Nandan MO, Hisamuddin IM, Dalton WB, Yang VW. |
Oncogene. 2005 Jun 9;24(25):4017-25. |
PMID 15806166 |
Requirement of Kruppel-like factor 4 in preventing entry into mitosis following DNA damage. |
Yoon HS, Yang VW. |
J Biol Chem. 2004 Feb 6;279(6):5035-41. Epub 2003 Nov 19. |
PMID 14627709 |
Novel cross talk of Kruppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression. |
Zhang W, Chen X, Kato Y, Evans PM, Yuan S, Yang J, Rychahou PG, Yang VW, He X, Evers BM, Liu C. |
Mol Cell Biol. 2006 Mar;26(6):2055-64. |
PMID 16507986 |
The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/CIP1 promoter. |
Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS, Yang VW. |
J Biol Chem. 2000 Jun 16;275(24):18391-8. |
PMID 10749849 |
The gut-enriched Kruppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion. |
Zhang W, Shields JM, Sogawa K, Fujii-Kuriyama Y, Yang VW. |
J Biol Chem. 1998 Jul 10;273(28):17917-25. |
PMID 9651398 |
Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. |
Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE, Yang VW. |
Oncogene. 2004 Jan 15;23(2):395-402. |
PMID 14724568 |
WNT signaling in the normal intestine and colorectal cancer. |
de Lau W, Barker N, Clevers H. |
Front Biosci. 2007 Jan 1;12:471-91. (REVIEW) |
PMID 17127311 |
Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. |
van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H. |
Nature. 2005 Jun 16;435(7044):959-63. |
PMID 15959515 |
Citation |
This paper should be referenced as such : |
Ghaleb, AM ; Yang, VW |
KLF4 (Kruppel-like factor 4 (gut)) |
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):639-643. |
Free journal version : [ pdf ] [ DOI ] |
External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
© Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Feb 19 17:53:26 CET 2021 |
For comments and suggestions or contributions, please contact us