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Krüppel-like factors: Three fingers in control

Human Genomics volume 4, Article number: 263 (2010) Cite this article

Abstract

Krüppel-like factors (KLFs), members of the zinc-finger family of transcription factors capable of binding GC-rich sequences, have emerged as critical regulators of important functions all over the body. They are characterised by a highly conserved C-terminal DNA-binding motif containing three C2H2 zinc-finger domains, with variable N-terminal regulatory domains. Currently, there are 17 KLFs annotated in the human genome. In spite of their structural similarity to one another, the genes encoding different KLFs are scattered all over the genome. By virtue of their ability to activate and/or repress the expression of a large number of genes, KLFs regulate a diverse array of developmental events and cellular processes, such as erythropoiesis, cardiac remodelling, adipogenesis, maintenance of stem cells, epithelial barrier formation, control of cell proliferation and neoplasia, flow-mediated endothelial gene expression, skeletal and smooth muscle development, gluconeogenesis, monocyte activation, intestinal and conjunctival goblet cell development, retinal neuronal regeneration and neonatal lung development. Characteristic features, nomenclature, evolution and functional diversities of the human KLFs are reviewed here.

Introduction

Krüppel-like factors (KLFs) are members of the zinc-finger family of transcription factors named after their similarity to the Drosophila gap gene Krüppel[1]. KLFs are characterised by a DNA-binding motif containing three well-conserved C2H2 zinc-finger domains located in the carboxy terminal of the protein capable of binding GC-rich sequences, such as CACCC elements present in the proximal promoters of many eukaryotic genes [2–7]. The transcriptional regulatory domains located in the amino terminal of different KLFs are variable, resulting in their ability to interact with co-activators and/or co-repressors, culminating in the activation or repression of a given promoter activity. The presence of variable structural motifs outside of the DNA-binding domain of the KLF family members is reflected in their functional diversity [3, 8]. Characteristic features, nomenclature, evolution and functions of the human KLFs are reviewed here.

Characteristic features of the zinc-finger domain in KLFs

The 81-amino acid DNA-binding zinc-finger domain is highly conserved among the members of the KLF family, with more than 65 per cent amino acid sequence identity among the family members. The specific amino acids critical for DNA binding are highly conserved, imparting an ability to different KLFs that interact with similar cis-elements, such as GT boxes or GC-rich sequences like CACCC. The C2H2 zinc finger present in the KLFs consists of two short beta strands followed by an alpha helix. In the classical C2H2 zinc-finger domain, two conserved cysteines and histidines coordinate a zinc ion. The pattern of amino acid arrangement in a classical zinc finger is as follows: #-X-C-X(1-5)-C-X3-#-X5-#-X2-H-X(3-6)-[H/C], where C, H and X correspond to cysteine, histidine and any amino acid, respectively, and numbers indicate the number of residues separating the flanking amino acids. The amino acids that are important for the stable fold of the zinc finger are marked with the # symbol. The amino acid occupying the final position can be either histidine or cysteine. The linker sequence in between the zinc-finger domains (TGE(R/K)P(Y/F)X) is also highly conserved in KLF proteins [9].

Nomenclature of KLFs

The nomenclature of KLFs has evolved over the years. KLFs were initially named after the tissue in which they were detected or highly expressed, such as erythroid KLF (EKLF or KLF1),[10] lung KLF (LKLF or KLF2),[11] gut-enriched KLF (GKLF/EZF or KLF4),[12–15] and intestinal-enriched KLF (IKLF or KLF5; also called BTEB2) [16, 17]. A few other KLFs were named after the elements they bound, such as the core promoter-binding protein (CPBP/Zf9 or KLF6),[18, 19] basic transcription element-binding protein (BTEB1 or KLF9),[20] or by their physiological responses, such as transforming growth factor-β-inducible early genes 1 and 2 (TIEG1 and TIEG2 or KLF10 and KLF11, respectively) [21, 22]. Considering that the tissue expression of KLFs, the range of their nucleotide recognition sequences and their ability to regulate diverse functions is much broader than initially understood, the use of numerical nomenclature based on the chronological order of discovery (such as KLF1, KLF2, KLF3. . .) is recommended by the Human Genome Organization Gene Nomenclature Committee (HGNC) to avoid misleading connotations providing partial descriptions of their expression and/or function. A search of the HGNC website http://www.genenames.org/index.html for 'Krüppel-like factor' on 26th January 2010 identified 17 KLF genes in the human genome. Names, chromosomal locations, sequence accession IDs, previous symbols and aliases, if any, for these KLFs are given in Table 1. Several other related proteins, such as the members of the Sp family of proteins, GLI2, GLI3, and the pseudogene KLF7P, are not included in this list, for the sake of brevity.

Table 1 Names, chromosomal locations, number of exons, sequence accession IDs, previous symbols and aliases, if any, for different KLFs.
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Evolution of KLFs

KLFs are closely related to the Sp family of zinc-finger transcription factors, of which there are nine members in the human genome (Sp1-Sp9). Currently, there are 17 KLFs annotated in the human genome. The high level of conservation of structure and function of KLF proteins in different species is a reflection of their ancient evolutionary history. The 17 genes encoding different KLFs are scattered all over the human genome, and there are also 17 Klf genes in the mouse genome. This indicates that these genes are ancient and suggests the involvement of gene duplications and translocations in their evolution.

The exon-intron organisation of human KLF genes is not well conserved. For example, while KLF12 has eight exons, KLF14 is encoded on a single exon (Table 1). Based on an extensive phylogenetic analysis with the amino acid sequences of KLF proteins from different species, it was proposed that the mammalian KLF genes have evolved in two phases - the first in the chordate lineage, during the early emergence of vertebrates, and the second in the mammalian lineage [23]. This phylogenetic analysis also identified six different ascidian zinc-finger proteins as the ancestral genes for the distinct subgroups of vertebrate KLF genes [23]. In view of the intron-less nature of KLF14 and its homology with KLF16, it has been suggested that KLF14 is an ancient retrotransposed copy of KLF16[24]. Phylogenetic analysis of the 17 human KLF complete amino acid sequences by the neighbour-joining method using the ClustalW2 program http://www.ebi.ac.uk/Tools/es/cgi-bin/clustalw2 indicated that KLFs 5, 17 and 8 are related more to each other than to the rest of the KLFs, which are further grouped into two major clades (Figure 1). According to this analysis, KLFs 9 and 16 are the most recent KLFs to have diverged from each other, followed by KLFs 6 and 7 (Figure 1). This is consistent with the similar expression pattern, common ability to interact with mSin3A (a core component of a large multiprotein co-repressor complex with associated histone deacetylase enzymatic activity) and shared cellular function of cell cycle regulation attributed to KLFs 9 and 16 (Table 2).

Figure 1
figure 1

Phylogenetic tree generated using the complete amino acid sequence of human KLF proteins by ClustalW2 web-based program http://www.ebi.ac.uk/Tools/es/cgi-bin/clustalw2. Evolutionary distances are shown next to the corresponding names.

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Table 2 Expression pattern, interacting co-factors, effect on gene expression and known functions of different KLFs.
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Functions of KLFs

By virtue of their ability to activate and/or repress the expression of a large number of genes, KLFs regulate a diverse array of developmental events and cellular processes such as haematopoiesis,[75, 76] cardiac remodelling,[77] adipogenesis,[27, 31, 46, 78–82] maintenance of stem cells,[83–86] epithelial barrier formation,[87–90] control of cell proliferation and neoplasia,[91–93] flow-mediated endothelial gene expression,[94, 95] skeletal and smooth muscle development,[96] gluconeogenesis,[69] monocyte activation, intestinal and conjunctival goblet cell development,[33, 97] ocular surface integrity,[33, 34] retinal neuronal regeneration [98] and neonatal lung development [40] (Table 2). This functional diversity of KLFs is consistent with the variable amino terminal regulatory domains in different KLFs that allow interaction with a diverse array of co-factors. For example, KLFs 3, 8 and 12 interact with carboxy-terminal binding protein (CtBP) co-repressors through the PVDL(S/T) repressor domain, while KLFs 9, 10, 11, 13 and 16 interact with histone deacetylases (HDACs) through a Sin3 interaction domain (SID), both resulting in transcriptional repression. KLF4 interacts with co-activators such as p300 and CBP (cyclic-AMP-response-element-binding-protein-binding-protein) to mediate transcriptional activation. KLF4 also has the ability to interact with HDACs, to repress transcription. The functional diversity of KLFs results in interesting conflicts, wherein different KLFs have antagonistic effect(s) on individual cellular processes. For example, KLF4 suppresses cell proliferation, while KLF5 promotes it. Similarly, adipogenesis is supported by KLFs 4, 5 and 15, but is suppressed by KLFs 2 and 3.

Future directions

A large body of work over the past 25 years has established the KLFs as critical regulators of diverse functions in many parts of the body. In spite of this progress in our understanding of the properties of KLFs, much remains to be uncovered. In order fully to understand the properties of KLFs in diverse spatio-temporal contexts and physiological conditions, it is crucial to identify (a) the co-factors that they interact with; (b) their target genes; (c) the signal transduction pathways by which they are regulated; and (d) their unique tissue-specific roles using conditional knockouts. It is expected that these avenues of research will lead to exciting discoveries regarding the involvement of KLFs in human health and disease.

References

  1. Wieschaus E, Nusslein-Volhard C, Kluding H: Kruppel, A gene whose activity is required early in the zygotic genome for normal embryonic segmentation. Dev Biol. 1984, 104: 172-186. 10.1016/0012-1606(84)90046-0.

    Article  CAS  PubMed  Google Scholar 

  2. Black AR, Black JD, Azizkhan-Clifford J: Sp1 and Kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol. 2001, 188: 143-160. 10.1002/jcp.1111.

    Article  CAS  PubMed  Google Scholar 

  3. Dang DT, Pevsner J, Yang VW: The biology of the mammalian Kruppel-like family of transcription factors. Int J Biochem Cell Biol. 2000, 32: 1103-1121. 10.1016/S1357-2725(00)00059-5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kaczynski J, Cook T, Urrutia R: Sp1- and Kruppel-like transcription factors. Genome Biol. 2003, 4: 206-10.1186/gb-2003-4-2-206.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Pearson R, Fleetwood J, Eaton S, Crossley M, et al: Kruppel-like transcription factors: A functional family. Int J Biochem Cell Biol. 2008, 40: 1996-2001. 10.1016/j.biocel.2007.07.018.

    Article  CAS  PubMed  Google Scholar 

  6. Suske G, Bruford E, Philipsen S: Mammalian SP/KLF transcription factors: Bring in the family. Genomics. 2005, 85: 551-556. 10.1016/j.ygeno.2005.01.005.

    Article  CAS  PubMed  Google Scholar 

  7. Turner J, Crossley M: Mammalian Kruppel-like transcription factors: More than just a pretty finger. Trends Biochem Sci. 1999, 24: 236-240. 10.1016/S0968-0004(99)01406-1.

    Article  CAS  PubMed  Google Scholar 

  8. Geiman DE, Ton-That H, Johnson JM, Yang VW: Transactivation and growth suppression by the gut-enriched Kruppel-like factor (Kruppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction. Nucleic Acids Res. 2000, 28: 1106-1113. 10.1093/nar/28.5.1106.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Schuh R, Aicher W, Gaul U, Cote S, et al: A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Kruppel, a Drosophila segmentation gene. Cell. 1986, 47: 1025-1032. 10.1016/0092-8674(86)90817-2.

    Article  CAS  PubMed  Google Scholar 

  10. Miller IJ, Bieker JJ: A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Kruppel family of nuclear proteins. Mol Cell Biol. 1993, 13: 2776-2786.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Anderson KP, Kern CB, Crable SC, Lingrel JB: Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Kruppel-like factor: Identification of a new multigene family. Mol Cell Biol. 1995, 15: 5957-5965.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Shields JM, Yang VW: Identification of the DNA sequence that interacts with the gut-enriched Kruppel-like factor. Nucleic Acids Res. 1998, 26: 796-802. 10.1093/nar/26.3.796.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Shields JM, Yang VW: Two potent nuclear localization signals in the gut-enriched Kruppel-like factor define a subfamily of closely related Kruppel proteins. J Biol Chem. 1997, 272: 18504-18507. 10.1074/jbc.272.29.18504.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Shields JM, Christy RJ, Yang VW: Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem. 1996, 271: 20009-20017. 10.1074/jbc.271.33.20009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B: A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J Biol Chem. 1996, 271: 31384-31390. 10.1074/jbc.271.49.31384.

    Article  CAS  PubMed  Google Scholar 

  16. Sogawa K, Imataka H, Yamasaki Y, Kusume H, et al: cDNA cloning and transcriptional properties of a novel GC box-binding protein, BTEB2. Nucleic Acids Res. 1993, 21: 1527-1532. 10.1093/nar/21.7.1527.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Conkright MD, Wani MA, Anderson KP, Lingrel JB: A gene encoding an intestinal-enriched member of the Kruppel-like factor family expressed in intestinal epithelial cells. Nucleic Acids Res. 1999, 27: 1263-1270. 10.1093/nar/27.5.1263.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Koritschoner NP, Bocco JL, Panzetta-Dutari GM, Dumur CI, et al: A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. J Biol Chem. 1997, 272: 9573-9580. 10.1074/jbc.272.14.9573.

    Article  CAS  PubMed  Google Scholar 

  19. Ratziu V, Lalazar A, Wong L, Dang Q, et al: Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Proc Natl Acad Sci USA. 1998, 95: 9500-9505. 10.1073/pnas.95.16.9500.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Imataka H, Sogawa K, Yasumoto K, Kikuchi Y, et al: Two regulatory proteins that bind to the basic transcription element (BTE), a GC box sequence in the promoter region of the rat P-4501A1 gene. EMBO J. 1992, 11: 3663-3671.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Blok LJ, Grossmann ME, Perry JE, Tindall DJ: Characterization of an early growth response gene, which encodes a zinc finger transcription factor, potentially involved in cell cycle regulation. Mol Endocrinol. 1995, 9: 1610-1620. 10.1210/me.9.11.1610.

    CAS  PubMed  Google Scholar 

  22. Cook T, Gebelein B, Mesa K, Mladek A, et al: Molecular cloning and characterization of TIEG2 reveals a new subfamily of transforming growth factor-beta-inducible Sp1-like zinc finger-encoding genes involved in the regulation of cell growth. J Biol Chem. 1998, 273: 25929-25936. 10.1074/jbc.273.40.25929.

    Article  CAS  PubMed  Google Scholar 

  23. Chen Z, Lei T, Chen X, Zhang J, et al: Porcine KLF gene family: Structure, mapping, and phylogenetic analysis. Genomics. 2009, 95: 111-119.

    Article  PubMed  Google Scholar 

  24. Parker-Katiraee L, Carson AR, Yamada T, Arnaud P, et al: Identification of the imprinted KLF14 transcription factor undergoing human-specific accelerated evolution. PLoS Genet. 2007, 3: e65-10.1371/journal.pgen.0030065.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Hodge D, Coghill E, Keys J, Maguire T, et al: A global role for EKLF in definitive and primitive erythropoiesis. Blood. 2006, 107: 3359-3370. 10.1182/blood-2005-07-2888.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Tallack MR, Keys JR, Humbert PO, Perkins AC: EKLF/KLF1 controls cell cycle entry via direct regulation of E2f2. J Biol Chem. 2009, 284: 20966-20974. 10.1074/jbc.M109.006346.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Banerjee SS, Feinberg MW, Watanabe M, Gray S, et al: The Kruppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-gamma expression and adipogenesis. J Biol Chem. 2003, 278: 2581-2584. 10.1074/jbc.M210859200.

    Article  PubMed  Google Scholar 

  28. Zhang X, Srinivasan SV, Lingrel JB: WWP1-dependent ubiquitination and degradation of the lung Kruppel-like factor, KLF2. Biochem Biophys Res Commun. 2004, 316: 139-148. 10.1016/j.bbrc.2004.02.033.

    Article  CAS  PubMed  Google Scholar 

  29. Sebzda E, Zou Z, Lee JS, Wang T, et al: Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat Immunol. 2008, 9: 292-300. 10.1038/ni1565.

    Article  CAS  PubMed  Google Scholar 

  30. Das H, Kumar A, Lin Z, Patino WD, et al: Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci USA. 2006, 103: 6653-6658. 10.1073/pnas.0508235103.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Sue N, Jack BH, Eaton SA, Pearson RC, et al: Targeted disruption of the basic Kruppel-like factor gene (Klf3) reveals a role in adipogenesis. Mol Cell Biol. 2008, 28: 3967-3978. 10.1128/MCB.01942-07.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Turner J, Nicholas H, Bishop D, Matthews JM, et al: The LIM protein FHL3 binds basic Kruppel-like factor/Kruppel-like factor 3 and its co-repressor C-terminal-binding protein 2. J Biol Chem. 2003, 278: 12786-12795. 10.1074/jbc.M300587200.

    Article  CAS  PubMed  Google Scholar 

  33. Swamynathan SK, Katz JP, Kaestner KH, Ashery-Padan R, et al: Conditional deletion of the mouse Klf4 gene results in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells. Mol Cell Biol. 2007, 27: 182-194. 10.1128/MCB.00846-06.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Swamynathan SK, Davis J, Piatigorsky J: Identification of candidate Klf4 target genes reveals the molecular basis of the diverse regulatory roles of Klf4 in the mouse cornea. Invest Ophthalmol Vis Sci. 2008, 49: 3360-3370. 10.1167/iovs.08-1811.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Evans PM, Chen X, Zhang W, Liu C: KLF4 interacts with beta-catenin/TCF4 and blocks p300/CBP recruitment by beta-catenin. Mol Cell Biol. 2010, 30: 372-381. 10.1128/MCB.00063-09.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Evans PM, Zhang W, Chen X, Yang J, et al: Kruppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation. J Biol Chem. 2007, 282: 33994-34002. 10.1074/jbc.M701847200.

    Article  CAS  PubMed  Google Scholar 

  37. Wei Z, Yan Y, Zhang P, Andrianakos R, et al: Klf4 interacts directly with Oct4 and Sox2 to promote reprogramming. Stem Cells. 2009, 27: 2969-2978.

    Article  CAS  PubMed  Google Scholar 

  38. Wei D, Kanai M, Jia Z, Le X, Xie K: Kruppel-like factor 4 induces p27Kip1 expression in and suppresses the growth and metastasis of human pancreatic cancer cells. Cancer Res. 2008, 68: 4631-4639. 10.1158/0008-5472.CAN-07-5953.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Young RD, Swamynathan SK, Boote C, Mann M, et al: Stromal edema in klf4 conditional null mouse cornea is associated with altered collagen fibril organization and reduced proteoglycans. Invest Ophthalmol Vis Sci. 2009, 50: 4155-4161. 10.1167/iovs.09-3561.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Wan H, Luo F, Wert SE, Zhang L, et al: Kruppel-like factor 5 is required for perinatal lung morphogenesis and function. Development. 2008, 135: 2563-2572. 10.1242/dev.021964.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Zhu N, Gu L, Findley HW, Chen C, et al: KLF5 Interacts with p53 in regulating survivin expression in acute lymphoblastic leukemia. J Biol Chem. 2006, 281: 14711-14718. 10.1074/jbc.M513810200.

    Article  CAS  PubMed  Google Scholar 

  42. Matsumura T, Suzuki T, Aizawa K, Munemosa Y, et al: The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction. J Biol Chem. 2005, 280: 12123-12129.

    Article  CAS  PubMed  Google Scholar 

  43. Suzuki T, Nishi T, Nagino T, Sasaki K, et al: Functional interaction between the transcription factor Kruppel-like factor 5 and poly(ADP-ribose) polymerase-1 in cardiovascular apoptosis. J Biol Chem. 2007, 282: 9895-9901. 10.1074/jbc.M608098200.

    Article  CAS  PubMed  Google Scholar 

  44. Du JX, Bialkowska AB, McConnell BB, Yang VW: SUMOylation regulates nuclear localization of Kruppel-like factor 5. J Biol Chem. 2008, 283: 31991-32002. 10.1074/jbc.M803612200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Du JX, Yun CC, Bialkowska A, Yang VW: Protein inhibitor of activated STAT1 interacts with and up-regulates activities of the pro-proliferative transcription factor Kruppel-like factor 5. J Biol Chem. 2007, 282: 4782-4793.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Li D, Yea S, Li S, Chen Z, et al: Kruppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1. J Biol Chem. 2005, 280: 26941-26952. 10.1074/jbc.M500463200.

    Article  CAS  PubMed  Google Scholar 

  47. Smaldone S, Laub F, Else C, Dragomir C, et al: Identification of MoKA, a novel F-box protein that modulates Kruppel-like transcription factor 7 activity. Mol Cell Biol. 2004, 24: 1058-1069. 10.1128/MCB.24.3.1058-1069.2004.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Smaldone S, Ramirez F: Multiple pathways regulate intra-cellular shuttling of MoKA, a co-activator of transcription factor KLF7. Nucleic Acids Res. 2006, 34: 5060-5068. 10.1093/nar/gkl659.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Laub F, Lei L, Sumiyoshi H, Kajimura D, et al: Transcription factor KLF7 is important for neuronal morphogenesis in selected regions of the nervous system. Mol Cell Biol. 2005, 25: 5699-5711. 10.1128/MCB.25.13.5699-5711.2005.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Lei L, Laub F, Lush M, Romera M, et al: The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons. Genes Dev. 2005, 19: 1354-1364. 10.1101/gad.1227705.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Lei L, Zhou J, Lin L, Parada LF: Brn3a and Klf7 cooperate to control TrkA expression in sensory neurons. Dev Biol. 2006, 300: 758-769. 10.1016/j.ydbio.2006.08.062.

    Article  CAS  PubMed  Google Scholar 

  52. van Vliet J, Turner J, Crossley M: Human Kruppel-like factor 8: A CACCC-box binding protein that associates with CtBP and represses transcription. Nucleic Acids Res. 2000, 28: 1955-1962. 10.1093/nar/28.9.1955.

    Article  CAS  PubMed  Google Scholar 

  53. Wang X, Zhao J: KLF8 transcription factor participates in oncogenic transformation. Oncogene. 2007, 26: 456-461. 10.1038/sj.onc.1209796.

    Article  PubMed  Google Scholar 

  54. Wang X, Zheng M, Liu G, Xia W, et al: Kruppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res. 2007, 67: 7184-7193. 10.1158/0008-5472.CAN-06-4729.

    Article  CAS  PubMed  Google Scholar 

  55. Zhao J, Bian ZC, Yee K, Chen BP, et al: Identification of transcription factor KLF8 as a downstream target of focal adhesion kinase in its regulation of cyclin D1 and cell cycle progression. Mol Cell. 2003, 11: 1503-1515. 10.1016/S1097-2765(03)00179-5.

    Article  CAS  PubMed  Google Scholar 

  56. Simmen FA, Su Y, Xiao R, Zeng Z, et al: The Kruppel-like factor 9 (KLF9) network in HEC-1-A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF9 expression. Reprod Biol Endocrinol. 2008, 6: 41-10.1186/1477-7827-6-41.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Simmen FA, Xiao R, Velarde MC, Nicholson RD, et al: Dysregulation of intestinal crypt cell proliferation and villus cell migration in mice lacking Kruppel-like factor 9. Am J Physiol Gastrointest Liver Physiol. 2007, 292: G1757-G1769. 10.1152/ajpgi.00013.2007.

    Article  CAS  PubMed  Google Scholar 

  58. Cayrou C, Denver RJ, Puymirat J: Suppression of the basic transcription element-binding protein in brain neuronal cultures inhibits thyroid hormone-induced neurite branching. Endocrinology. 2002, 143: 2242-2249. 10.1210/en.143.6.2242.

    Article  CAS  PubMed  Google Scholar 

  59. Cook T, Urrutia R: TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth. Am J Physiol Gastrointest Liver Physiol. 2000, 278: G513-G521.

    CAS  PubMed  Google Scholar 

  60. Fernandez-Zapico ME, Mladek A, Ellenrieder V, Folch-Puy E, et al: An mSin3A interaction domain links the transcriptional activity of KLF11 with its role in growth regulation. EMBO J. 2003, 22: 4748-4758. 10.1093/emboj/cdg470.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Fernandez-Zapico ME, van Velkinburgh JC, Gutierrez-Aguilar R, Neve B, et al: MODY7 gene, KLF11, is a novel p300-dependent regulator of Pdx-1 (MODY4) transcription in pancreatic islet beta cells. J Biol Chem. 2009, 284: 36482-36490. 10.1074/jbc.M109.028852.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Schuierer M, Hilger-Eversheim K, Dobner T, Bosserhoff AK, et al: Induction of AP-2alpha expression by adenoviral infection involves inactivation of the AP-2rep transcriptional corepressor CtBP1. J Biol Chem. 2001, 276: 27944-27949. 10.1074/jbc.M100070200.

    Article  CAS  PubMed  Google Scholar 

  63. Nakamura Y, Migita T, Hosoda F, Okada N, et al: Kruppel-like factor 12 plays a significant role in poorly differentiated gastric cancer progression. Int J Cancer. 2009, 125: 1859-1867. 10.1002/ijc.24538.

    Article  CAS  PubMed  Google Scholar 

  64. Kaczynski J, Zhang JS, Ellenrieder V, Conley A, et al: The Sp1-like protein BTEB3 inhibits transcription via the basic transcription element box by interacting with mSin3A and HDAC-1 co-repressors and competing with Sp1. J Biol Chem. 2001, 276: 36749-36756. 10.1074/jbc.M105831200.

    Article  CAS  PubMed  Google Scholar 

  65. Kaczynski JA, Conley AA, Fernandez Zapico M, Delgado SM, et al: Functional analysis of basic transcription element (BTE)-binding protein (BTEB) 3 and BTEB4, a novel Sp1-like protein, reveals a subfamily of transcriptional repressors for the BTE site of the cytochrome P4501A1 gene promoter. Biochem J. 2002, 366: 873-882.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Chasman DI, Pare G, Mora S, Hopewell JC, et al: Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet. 2009, 5: e1000730-10.1371/journal.pgen.1000730.

    Article  PubMed Central  PubMed  Google Scholar 

  67. Stacey SN, Sulem P, Masson G, Gudjonsson SA, et al: New common variants affecting susceptibility to basal cell carcinoma. Nat Genet. 2009, 41: 909-914. 10.1038/ng.412.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Truty MJ, Lomberk G, Fernandez-Zapico ME, Urrutia R: Silencing of the transforming growth factor-beta (TGFbeta) receptor II by Kruppel-like factor 14 underscores the importance of a negative feedback mechanism in TGFbeta signaling. J Biol Chem. 2009, 284: 6291-6300.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Gray S, Wang B, Orihuela Y, Hong EG, et al: Regulation of gluconeogenesis by Kruppel-like factor 15. Cell Metab. 2007, 5: 305-312. 10.1016/j.cmet.2007.03.002.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Yamamoto J, Ikeda , Iguchi H, Fujino T, et al: A Kruppel-like factor KLF15 contributes fasting-induced transcriptional activation of mitochondrial acetyl-CoA synthetase gene AceCS2. J Biol Chem. 2004, 279: 16954-16962. 10.1074/jbc.M312079200.

    Article  CAS  PubMed  Google Scholar 

  71. Fisch S, Gray S, Heymans S, Halder SM, et al: Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy. Proc Natl Acad Sci USA. 2007, 104: 7074-7079. 10.1073/pnas.0701981104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Sakaguchi M, Sonegawa H, Nukui T, Sakaguchi Y, et al: Bifurcated converging pathways for high Ca2+- and TGFbeta-induced inhibition of growth of normal human keratinocytes. Proc Natl Acad Sci USA. 2005, 102: 13921-13926. 10.1073/pnas.0500630102.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. van Vliet J, Crofts LA, Quinlan KG, Czolij R, et al: Human KLF17 is a new member of the Sp/KLF family of transcription factors. Genomics. 2006, 87: 474-482. 10.1016/j.ygeno.2005.12.011.

    Article  CAS  PubMed  Google Scholar 

  74. Gumireddy K, Li A, Gimotty PA, Klein-Szanto AJ, et al: KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Nat Cell Biol. 2009, 11: 1297-1304. 10.1038/ncb1974.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Nuez B, Michalovich D, Bygrave A, Ploemacher R, et al: Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature. 1995, 375: 316-318. 10.1038/375316a0.

    Article  CAS  PubMed  Google Scholar 

  76. Drissen R, von Lindern M, Kolbus A, Driegen S, et al: The erythroid phenotype of EKLF-null mice: Defects in hemoglobin metabolism and membrane stability. Mol Cell Biol. 2005, 25: 5205-5214. 10.1128/MCB.25.12.5205-5214.2005.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Shindo T, Manabe I, Fukushima Y, Tobe K, et al: Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med. 2002, 8: 856-863.

    CAS  PubMed  Google Scholar 

  78. Brey CW, Nelder MP, Hailemariam T, Gaugler R, et al: Kruppel-like family of transcription factors: An emerging new frontier in fat biology. Int J Biol Sci. 2009, 5: 622-636.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Eaton SA, Funnell AP, Sue N, Nicholas H, et al: A network of Kruppel-like Factors (Klfs) (2008), 'Klf8 is repressed by Klf3 and activated by Klf1 in vivo. J Biol Chem. 2008, 283: 26937-26947. 10.1074/jbc.M804831200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Birsoy K, Chen Z, Friedman J: Transcriptional regulation of adipogenesis by KLF4. Cell Metab. 2008, 7: 339-347. 10.1016/j.cmet.2008.02.001.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Oishi Y, Manabe I, Tobe K, Tsushima K, et al: Kruppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation. Cell Metab. 2005, 1: 27-39. 10.1016/j.cmet.2004.11.005.

    Article  CAS  PubMed  Google Scholar 

  82. Mori T, Sakaue H, Iguchi H, Gomi H, et al: Role of Kruppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis. J Biol Chem. 2005, 280: 12867-12875.

    Article  CAS  PubMed  Google Scholar 

  83. Ema M, Mori D, Niwa H, Hasegawa Y, et al: Kruppel-like factor 5 is essential for blastocyst development and the normal self-renewal of mouse ESCs. Cell Stem Cell. 2008, 3: 555-567. 10.1016/j.stem.2008.09.003.

    Article  CAS  PubMed  Google Scholar 

  84. Jiang J, Chan YS, Loh YH, Cai J, et al: A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol. 2008, 10: 353-360. 10.1038/ncb1698.

    Article  PubMed  Google Scholar 

  85. Park IH, Zhao R, West JA, Yabuuchi A, et al: Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2008, 451: 141-146. 10.1038/nature06534.

    Article  CAS  PubMed  Google Scholar 

  86. Parisi S, Passaro F, Aloia L, Manabe I, et al: Klf5 is involved in self-renewal of mouse embryonic stem cells. J Cell Sci. 2008, 121: 2629-2634. 10.1242/jcs.027599.

    Article  CAS  PubMed  Google Scholar 

  87. Patel S, Xi ZF, Seo EY, McGaughey D, et al: Klf4 and corticosteroids activate an overlapping set of transcriptional targets to accelerate in utero epidermal barrier acquisition. Proc Natl Acad Sci USA. 2006, 103: 18668-18673. 10.1073/pnas.0608658103.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Jaubert J, Cheng J, Segre JA: Ectopic expression of kruppel like factor 4 (Klf4) accelerates formation of the epidermal permeability barrier. Development. 2003, 130: 2767-2777. 10.1242/dev.00477.

    Article  CAS  PubMed  Google Scholar 

  89. Segre JA, Bauer C, Fuchs E: Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet. 1999, 22: 356-360. 10.1038/11926.

    Article  CAS  PubMed  Google Scholar 

  90. McConnell BB, Ghaleb AM, Nandan MO, Yang VW: The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology. Bioessays. 2007, 29: 549-557. 10.1002/bies.20581.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Dong JT, Chen C: Essential role of KLF5 transcription factor in cell proliferation and differentiation and its implications for human diseases. Cell Mol Life Sci. 2009, 66: 2691-2706. 10.1007/s00018-009-0045-z.

    Article  CAS  PubMed  Google Scholar 

  92. Evans PM, Liu C: Roles of Kruppel-like factor 4 in normal homeostasis, cancer and stem cells. Acta Biochim Biophys Sin (Shanghai). 2008, 40: 554-564. 10.1111/j.1745-7270.2008.00439.x.

    Article  CAS  Google Scholar 

  93. Rowland BD, Peeper DS: KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer. 2006, 6: 11-23. 10.1038/nrc1780.

    Article  CAS  PubMed  Google Scholar 

  94. De Val S, Black BL: Transcriptional control of endothelial cell development. Dev Cell. 2009, 16: 180-195. 10.1016/j.devcel.2009.01.014.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Boon RA, Horrevoets AJ: Key transcriptional regulators of the vasoprotective effects of shear stress. Hamostaseologie. 2009, 29: 39-43.

    CAS  PubMed  Google Scholar 

  96. Haldar SM, Ibrahim OA, Jain MK: Kruppel-like factors (KLFs) in muscle biology. J Mol Cell Cardiol. 2007, 43: 1-10. 10.1016/j.yjmcc.2007.04.005.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Katz JP, Perreault N, Goldstein BG, Lee CS, et al: The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development. 2002, 129: 2619-2628.

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Moore DL, Blackmore MG, Hu Y, Kaestner KH, et al: KLF family members regulate intrinsic axon regeneration ability. Science. 2009, 326: 298-301. 10.1126/science.1175737.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgements

I apologise to those colleagues whose work could not be cited owing to space constraints. Work in the author's laboratory was supported by the NEI career development award 1K22EY016875-01, NEI core grant for vision research (5P30 EY08098-19), Research to Prevent Blindness and the Eye and Ear Foundation, Pittsburgh, PA, USA.

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  1. Department of Ophthalmology, University of Pittsburgh School of Medicine, Eye and Ear Institute, 203 Lothrop Street, Room 1025, Pittsburgh, PA, 15213, USA

    Shivalingappa K Swamynathan

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Swamynathan, S.K. Krüppel-like factors: Three fingers in control. Hum Genomics 4, 263 (2010). https://doi.org/10.1186/1479-7364-4-4-263

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Keywords

  • gene expression
  • zinc-finger
  • transcription factor
  • Krüppel-like factor
  • DNA-binding

Human Genomics

ISSN: 1479-7364