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Wikipedia

KLF4

December 14, 2023

Kruppel-like factor 4 (KLF4; gut-enriched Krüppel-like factor or GKLF) is a member of the KLF family of zinc finger transcription factors, which belongs to the relatively large family of SP1-like transcription factors.[5][6][7] KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including colorectal cancer.[8] It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2.[6] It has two nuclear localization sequences that signals it to localize to the nucleus.[9] In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs).

KLF4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKLF4, EZF, GKLF, Kruppel-like factor 4 (gut), Kruppel like factor 4
External IDsOMIM: 602253 MGI: 1342287 HomoloGene: 3123 GeneCards: KLF4
Orthologs
SpeciesHumanMouse
Entrez

9314

16600

Ensembl

ENSG00000136826

ENSMUSG00000003032

UniProt

O43474

Q60793

RefSeq (mRNA)

NM_001314052
NM_004235

NM_010637

RefSeq (protein)

NP_001300981
NP_004226

NP_034767

Location (UCSC)Chr 9: 107.48 – 107.49 MbChr 4: 55.53 – 55.53 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

In humans, the protein is 513 amino acids, with a predicted molecular weight of approximately 55kDa, and is encoded by the KLF4 gene.[10] The KLF4 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.[11] KLF4 was first identified in 1996.[12]

Interactions edit

KLF4 can activate transcription by interacting via it N-terminus with specific transcriptional co-activators, such as p300-CBP coactivator family.[13][14][15] Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence (9-12).[16][17][18][19] KLF4 has been shown to interact with CREB-binding protein.[20]

It was found that the transcription factor Klf4 present at the promoter of an enzymatic subunit of telomerase (TERT), where it formed a complex with β-catenin. Klf4 was required for accumulation of β-catenin at the Tert promoter but was unable to stimulate Tert expression in the absence of β-catenin.[21]

Function edit

KLF4 has diverse functions, and has been garnering attention in recent years because some of its functions are apparently contradicting, but mainly since the discovery of its integral role as one of four key factors that are essential for inducing pluripotent stem cells.[22][23] KLF4 is highly expressed in non-dividing cells and its overexpression induces cell cycle arrest.[12][24][25][26][27] KLF4 is particularly important in preventing cell division when the DNA is damaged.[24][26][27][28] KLF4 is also important in regulating centrosome number and chromosome number (genetic stability),[29][30][31] and in promoting cell survival.[32][33][34][35][36][37] However, some studies have revealed that under certain conditions KLF4 may switch its role from pro-cell survival to pro-cell death.[36][38][39][40]

KLF4 is expressed in the cells that are non-dividing and are terminally differentiated in the intestinal epithelium, where KLF4 is important in the regulation of intestinal epithelium homeostasis (terminal cell differentiation and proper localization of the different intestinal epithelium cell types).[41][42][43][44] In the intestinal epithelium, KLF4 is an important regulator of Wnt signaling pathway genes of genes regulating differentiation.[44]

KLF4 is expressed in a variety of tissues and organs such as: the cornea where it is required for epithelial barrier function[45][46] and is a regulator of genes required for corneal homeostasis;[47] the skin where it is required for the development of skin permeability barrier function;[48][49][50] the bone and teeth tissues where it regulates normal skeletal development;[51][52][53][54] epithelial cell of the mouse male and female reproductive tract[55] where in the males it is important for proper spermatogenesis;[56][57][58] vascular endothelial cells[59] where it is critical in preventing vascular leakage in response to inflammatory stimuli;[60] white blood cells where it mediates inflammatory responses cellular differentiation[61][62][63][64] and proliferation;[64][65] the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem (iPS) cells to renal lineage in vitro[66] and its dysregulation has been linked to some renal pathologies.[67][68][69]

Roles in diseases edit

Several lines of evidence have shown that KLF4 role in disease is context dependent where under certain conditions it may play one role and under different conditions it may assume a complete opposite role.

KLF4 is an anti-tumorigenic factor and its expression is often lost in various human cancer types, such as Colorectal cancer,[70] gastric cancer,[71] esophageal squamous cell carcinoma,[33] intestinal cancer,[72] prostate cancer,[73] bladder cancer[74] and lung cancer.[75]

However, in some cancer types KLF4 may act as a tumor promoter where increased KLF4 expression has been reported, such as in oral squamous cell carcinoma[76] and in primary breast ductal carcinoma.[77] Also, overexpression of KLF4 in skin resulted in hyperplasia and dysplasia,[78] which lead to the development of squamous cell carcinoma.[79] Similar finding in esophageal epithelium was observed, where overexpression of KLF4 resulted in increased inflammation that eventually lead to the development of esophageal squamous cell cancer in mice.[80]

The role of KLF4 in Epithelial–mesenchymal transition (EMT) is also controversial. It was shown to stimulate EMT in some systems by promoting/maintaining stemness of cancer cells, as is the case in pancreatic cancer,[81][82][83] head and neck cancer,[84] endometrial cancer,[85] nasopharyngeal cancer,[86] prostate cancer[87] and non-small lung cancer.[88] Under conditions of TGFβ-induced EMT KLF4 was shown to suppress EMT in the same systems where it was shown to promote EMT, such as prostate cancer[89] and pancreatic cancer.[90] Additionally, KLF4 was shown to suppress EMT in epidermal cancer,[91] breast cancer,[36] lung cancer,[92] cisplatin-resistant nasopharyngeal carcinoma cells,[93] and in hepatocellular carcinoma cells.[citation needed]

KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization[94] and plaque formation in atherosclerosis.[95][96][97] It up-regulates Apolipoprotein E, which is an anti-atherosclerotic factor.[96] It is also involved in the regulation of angiogenesis. It may suppress angiogenesis by regulating NOTCH1 activity,[98] while in the central nervous system its overexpression leads to vascular dysplasia.[99]

KLF4 may promote inflammation by mediating NF-κB-dependent inflammatory pathway such as in macrophages,[18] esophageal epithelium[80] and in chemically-induced acute colitis in mice.[100] Additionally, KLF-4 downregulates TNF-α-induced VCAM1 expression by targeting and blocking the binding site of NF-κB to the VCAM1 promoter.[101]

However, KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro-inflammatory stimuli.[59]

KLF4 is essential for the cellular response to DNA damage. It is required for preventing cell cycle entry into mitosis following γ-irradiation-induced DNA damage,[26][27] in promoting DNA repair mechanisms (20) and in preventing the irradiated cell from undergoing programmed cell death (apoptosis) (23,25,26).[32][34][35] In one study, the in vivo importance of KLF4 in response to γ-irradiation-induced DNA damage was revealed where deletion of KLF4 specifically from the intestinal epithelium in mice lead to inability of the intestinal epithelium to regenerate and resulting in increased mortality of these mice.[35]

Importance in Stem cells edit

Takahashi and Yamanaka were the first to identify KLF4 as one of four factors ( oct-3/4 + sox2 + Klf4 + c-Myc ) that are required to induce mouse embryonic and adult fibroblasts into pluripotent stem cells (iPS).[23] This was also found to be true for adult human fibroblasts.[22] Since 2006 up to today, the work on clinically relevant research in stem cells and stem cell induction, has increased dramatically (more than 10,000 research articles, as compared to about 60 between years 1900 to 2005). In vivo functional studies on the role of KLF4 in stem cells are rare. Recently a group investigated the role of KLF4 in a particular population of intestinal stem cells, the Bmi1+ stem cells.[37] This population of intestinal stem cells: are normally slow dividing, are known to be resistant to radiation injury, and are the ones responsible for intestinal epithelium regeneration following radiation injury.[102] The study showed that in the intestine, following γ-irradiation-induced DNA damage, KLF4 may regulate epithelial regeneration by modulating the fate of Bmi1+((BMI1)) stem cells themselves, and consequently the development of Bmi1+ + intestinal stem cell-derived lineage.[37]

See also edit

Notes edit

References edit

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Further reading edit

  • Rowland BD, Peeper DS (January 2006). "KLF4, p21 and context-dependent opposing forces in cancer". Nature Reviews. Cancer. 6 (1): 11–23. doi:10.1038/nrc1780. PMID 16372018. S2CID 41981721.
  • Shields JM, Christy RJ, Yang VW (August 1996). "Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest". The Journal of Biological Chemistry. 271 (33): 20009–17. doi:10.1074/jbc.271.33.20009. PMC 2330254. PMID 8702718.
  • Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B (December 1996). "A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells". The Journal of Biological Chemistry. 271 (49): 31384–90. doi:10.1074/jbc.271.49.31384. PMID 8940147.
  • 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 (January 1998). "Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains". The Journal of Biological Chemistry. 273 (2): 1026–31. doi:10.1074/jbc.273.2.1026. PMID 9422764.
  • Zhang W, Shields JM, Sogawa K, Fujii-Kuriyama Y, Yang VW (July 1998). "The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion". The Journal of Biological Chemistry. 273 (28): 17917–25. doi:10.1074/jbc.273.28.17917. PMC 2275057. PMID 9651398.
  • Foster KW, Ren S, Louro ID, Lobo-Ruppert SM, McKie-Bell P, Grizzle W, Hayes MR, Broker TR, Chow LT, Ruppert JM (June 1999). "Oncogene expression cloning by retroviral transduction of adenovirus E1A-immortalized rat kidney RK3E cells: transformation of a host with epithelial features by c-MYC and the zinc finger protein GKLF". Cell Growth & Differentiation. 10 (6): 423–34. PMID 10392904.
  • Segre JA, Bauer C, Fuchs E (August 1999). "Klf4 is a transcription factor required for establishing the barrier function of the skin". Nature Genetics. 22 (4): 356–60. doi:10.1038/11926. PMID 10431239. S2CID 3014700.
  • Geiman DE, Ton-That H, Johnson JM, Yang VW (March 2000). "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 Research. 28 (5): 1106–13. doi:10.1093/nar/28.5.1106. PMC 102607. PMID 10666450.
  • Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS, Yang VW (June 2000). "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. 275 (24): 18391–8. doi:10.1074/jbc.C000062200. PMC 2231805. PMID 10749849.
  • Okano J, Opitz OG, Nakagawa H, Jenkins TD, Friedman SL, Rustgi AK (May 2000). "The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact". FEBS Letters. 473 (1): 95–100. doi:10.1016/S0014-5793(00)01468-X. PMID 10802067. S2CID 34923598.
  • Higaki Y, Schullery D, Kawata Y, Shnyreva M, Abrass C, Bomsztyk K (June 2002). "Synergistic activation of the rat laminin gamma1 chain promoter by the gut-enriched Kruppel-like factor (GKLF/KLF4) and Sp1". Nucleic Acids Research. 30 (11): 2270–9. doi:10.1093/nar/30.11.2270. PMC 117209. PMID 12034813.
  • Chen ZY, Shie JL, Tseng CC (November 2002). "Gut-enriched Kruppel-like factor represses ornithine decarboxylase gene expression and functions as checkpoint regulator in colonic cancer cells". The Journal of Biological Chemistry. 277 (48): 46831–9. doi:10.1074/jbc.M204816200. PMID 12297499.
  • Yoon HS, Chen X, Yang VW (January 2003). "Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage". The Journal of Biological Chemistry. 278 (4): 2101–5. doi:10.1074/jbc.M211027200. PMC 2229830. PMID 12427745.
  • Wang N, Liu ZH, Ding F, Wang XQ, Zhou CN, Wu M (December 2002). "Down-regulation of gut-enriched Kruppel-like factor expression in esophageal cancer". World Journal of Gastroenterology. 8 (6): 966–70. doi:10.3748/wjg.v8.i6.966. PMC 4656400. PMID 12439907.
  • Chen X, Whitney EM, Gao SY, Yang VW (February 2003). "Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation". Journal of Molecular Biology. 326 (3): 665–77. doi:10.1016/S0022-2836(02)01449-3. PMC 2693487. PMID 12581631.
  • Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW (May 2003). "Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity". Oncogene. 22 (22): 3424–30. doi:10.1038/sj.onc.1206413. PMC 2275074. PMID 12776194.
  • Mao Z, Song S, Zhu Y, Yi X, Zhang H, Shang Y, Tong T (July 2003). "Transcriptional regulation of A33 antigen expression by gut-enriched Krüppel-like factor". Oncogene. 22 (28): 4434–43. doi:10.1038/sj.onc.1206508. PMID 12853980.
  • Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, Haga K, Asaka M, Ramirez F, Yoshida T (August 2003). "Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer". Biochemical and Biophysical Research Communications. 308 (2): 251–6. doi:10.1016/S0006-291X(03)01356-1. PMID 12901861.
  • Hinnebusch BF, Siddique A, Henderson JW, Malo MS, Zhang W, Athaide CP, Abedrapo MA, Chen X, Yang VW, Hodin RA (January 2004). "Enterocyte differentiation marker intestinal alkaline phosphatase is a target gene of the gut-enriched Kruppel-like factor". American Journal of Physiology. Gastrointestinal and Liver Physiology. 286 (1): G23-30. doi:10.1152/ajpgi.00203.2003. PMID 12919939.

External links edit

  • KLF4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • KLF4 microarray expression results and literature

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

December 14, 2023
klf4, kruppel, like, factor, enriched, krüppel, like, factor, gklf, member, family, zinc, finger, transcription, factors, which, belongs, relatively, large, family, like, transcription, factors, involved, regulation, proliferation, differentiation, apoptosis, . Kruppel like factor 4 KLF4 gut enriched Kruppel like factor or GKLF is a member of the KLF family of zinc finger transcription factors which belongs to the relatively large family of SP1 like transcription factors 5 6 7 KLF4 is involved in the regulation of proliferation differentiation apoptosis and somatic cell reprogramming Evidence also suggests that KLF4 is a tumor suppressor in certain cancers including colorectal cancer 8 It has three C2H2 zinc fingers at its carboxyl terminus that are closely related to another KLF KLF2 6 It has two nuclear localization sequences that signals it to localize to the nucleus 9 In embryonic stem cells ESCs KLF4 has been demonstrated to be a good indicator of stem like capacity It is suggested that the same is true in mesenchymal stem cells MSCs KLF4Available structuresPDBOrtholog search PDBe RCSBList of PDB id codes2WBS 2WBU 4M9EIdentifiersAliasesKLF4 EZF GKLF Kruppel like factor 4 gut Kruppel like factor 4External IDsOMIM 602253 MGI 1342287 HomoloGene 3123 GeneCards KLF4Gene location Human Chr Chromosome 9 human 1 Band9q31 2Start107 484 852 bp 1 End107 490 482 bp 1 Gene location Mouse Chr Chromosome 4 mouse 2 Band4 B3 4 29 76 cMStart55 527 143 bp 2 End55 532 466 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inhuman penissynovial jointskin of abdomenvulvajejunal mucosanipplegastric mucosaurethragumscavity of mouthTop expressed inepithelium of stomachmucous cell of stomachconjunctival fornixleft colonpyloric antrumintestinal villusbelly cordcervixstria vascularisskin of abdomenMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionDNA binding sequence specific DNA binding beta catenin binding phosphatidylinositol 3 kinase regulator activity DNA binding transcription factor activity zinc ion binding DNA binding transcription activator activity RNA polymerase II specific transcription factor binding cis regulatory region sequence specific DNA binding metal ion binding RNA polymerase II sequence specific DNA binding transcription factor recruiting activity protein binding nucleic acid binding double stranded DNA binding promoter specific chromatin binding RNA polymerase II cis regulatory region sequence specific DNA binding DNA binding transcription factor activity RNA polymerase II specific transcription coregulator binding histone deacetylase bindingCellular componentcytoplasm transcription regulator complex nucleoplasm chromatin nucleusBiological processnegative regulation of chemokine C X C motif ligand 2 production epidermal cell differentiation cellular response to retinoic acid negative regulation of protein kinase B signaling negative regulation of muscle hyperplasia negative regulation of smooth muscle cell proliferation positive regulation of protein metabolic process negative regulation of cysteine type endopeptidase activity involved in apoptotic process regulation of axon regeneration cellular response to peptide regulation of transcription DNA templated positive regulation of hemoglobin biosynthetic process response to retinoic acid somatic stem cell population maintenance cellular response to laminar fluid shear stress regulation of transcription by RNA polymerase II cell differentiation epidermis morphogenesis positive regulation of nitric oxide biosynthetic process cellular response to growth factor stimulus cellular response to organic cyclic compound post embryonic hemopoiesis negative regulation of transcription by RNA polymerase II transcription by RNA polymerase II response to organic substance negative regulation of gene expression negative regulation of response to cytokine stimulus transcription DNA templated negative regulation of DNA binding transcription factor activity negative regulation of phosphatidylinositol 3 kinase signaling stem cell population maintenance negative regulation of cell migration involved in sprouting angiogenesis positive regulation of gene expression negative regulation of cell migration regulation of cell population proliferation post embryonic camera type eye development regulation of phosphatidylinositol 3 kinase activity positive regulation of telomerase activity canonical Wnt signaling pathway negative regulation of ERK1 and ERK2 cascade regulation of cell differentiation mesodermal cell fate determination negative regulation of heterotypic cell cell adhesion negative regulation of transcription DNA templated negative regulation of NF kappaB transcription factor activity cellular response to cycloheximide negative regulation of inflammatory response fat cell differentiation positive regulation of transcription by RNA polymerase II negative regulation of cell population proliferation cellular response to hydrogen peroxide negative regulation of leukocyte adhesion to arterial endothelial cell positive regulation of core promoter binding cellular response to leukemia inhibitory factor negative regulation of angiogenesis pri miRNA transcription by RNA polymerase II negative regulation of G1 S transition of mitotic cell cycle positive regulation of transcription DNA templated positive regulation of sprouting angiogenesisSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez931416600EnsemblENSG00000136826ENSMUSG00000003032UniProtO43474Q60793RefSeq mRNA NM 001314052NM 004235NM 010637RefSeq protein NP 001300981NP 004226NP 034767Location UCSC Chr 9 107 48 107 49 MbChr 4 55 53 55 53 MbPubMed search 3 4 WikidataView Edit HumanView Edit MouseIn humans the protein is 513 amino acids with a predicted molecular weight of approximately 55kDa and is encoded by the KLF4 gene 10 The KLF4 gene is conserved in chimpanzee rhesus monkey dog cow mouse rat chicken zebrafish and frog 11 KLF4 was first identified in 1996 12 Contents 1 Interactions 2 Function 3 Roles in diseases 4 Importance in Stem cells 5 See also 6 Notes 7 References 8 Further reading 9 External linksInteractions editKLF4 can activate transcription by interacting via it N terminus with specific transcriptional co activators such as p300 CBP coactivator family 13 14 15 Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence 9 12 16 17 18 19 KLF4 has been shown to interact with CREB binding protein 20 It was found that the transcription factor Klf4 present at the promoter of an enzymatic subunit of telomerase TERT where it formed a complex with b catenin Klf4 was required for accumulation of b catenin at the Tert promoter but was unable to stimulate Tert expression in the absence of b catenin 21 Function editKLF4 has diverse functions and has been garnering attention in recent years because some of its functions are apparently contradicting but mainly since the discovery of its integral role as one of four key factors that are essential for inducing pluripotent stem cells 22 23 KLF4 is highly expressed in non dividing cells and its overexpression induces cell cycle arrest 12 24 25 26 27 KLF4 is particularly important in preventing cell division when the DNA is damaged 24 26 27 28 KLF4 is also important in regulating centrosome number and chromosome number genetic stability 29 30 31 and in promoting cell survival 32 33 34 35 36 37 However some studies have revealed that under certain conditions KLF4 may switch its role from pro cell survival to pro cell death 36 38 39 40 KLF4 is expressed in the cells that are non dividing and are terminally differentiated in the intestinal epithelium where KLF4 is important in the regulation of intestinal epithelium homeostasis terminal cell differentiation and proper localization of the different intestinal epithelium cell types 41 42 43 44 In the intestinal epithelium KLF4 is an important regulator of Wnt signaling pathway genes of genes regulating differentiation 44 KLF4 is expressed in a variety of tissues and organs such as the cornea where it is required for epithelial barrier function 45 46 and is a regulator of genes required for corneal homeostasis 47 the skin where it is required for the development of skin permeability barrier function 48 49 50 the bone and teeth tissues where it regulates normal skeletal development 51 52 53 54 epithelial cell of the mouse male and female reproductive tract 55 where in the males it is important for proper spermatogenesis 56 57 58 vascular endothelial cells 59 where it is critical in preventing vascular leakage in response to inflammatory stimuli 60 white blood cells where it mediates inflammatory responses cellular differentiation 61 62 63 64 and proliferation 64 65 the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem iPS cells to renal lineage in vitro 66 and its dysregulation has been linked to some renal pathologies 67 68 69 Roles in diseases editSeveral lines of evidence have shown that KLF4 role in disease is context dependent where under certain conditions it may play one role and under different conditions it may assume a complete opposite role KLF4 is an anti tumorigenic factor and its expression is often lost in various human cancer types such as Colorectal cancer 70 gastric cancer 71 esophageal squamous cell carcinoma 33 intestinal cancer 72 prostate cancer 73 bladder cancer 74 and lung cancer 75 However in some cancer types KLF4 may act as a tumor promoter where increased KLF4 expression has been reported such as in oral squamous cell carcinoma 76 and in primary breast ductal carcinoma 77 Also overexpression of KLF4 in skin resulted in hyperplasia and dysplasia 78 which lead to the development of squamous cell carcinoma 79 Similar finding in esophageal epithelium was observed where overexpression of KLF4 resulted in increased inflammation that eventually lead to the development of esophageal squamous cell cancer in mice 80 The role of KLF4 in Epithelial mesenchymal transition EMT is also controversial It was shown to stimulate EMT in some systems by promoting maintaining stemness of cancer cells as is the case in pancreatic cancer 81 82 83 head and neck cancer 84 endometrial cancer 85 nasopharyngeal cancer 86 prostate cancer 87 and non small lung cancer 88 Under conditions of TGFb induced EMT KLF4 was shown to suppress EMT in the same systems where it was shown to promote EMT such as prostate cancer 89 and pancreatic cancer 90 Additionally KLF4 was shown to suppress EMT in epidermal cancer 91 breast cancer 36 lung cancer 92 cisplatin resistant nasopharyngeal carcinoma cells 93 and in hepatocellular carcinoma cells citation needed KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization 94 and plaque formation in atherosclerosis 95 96 97 It up regulates Apolipoprotein E which is an anti atherosclerotic factor 96 It is also involved in the regulation of angiogenesis It may suppress angiogenesis by regulating NOTCH1 activity 98 while in the central nervous system its overexpression leads to vascular dysplasia 99 KLF4 may promote inflammation by mediating NF kB dependent inflammatory pathway such as in macrophages 18 esophageal epithelium 80 and in chemically induced acute colitis in mice 100 Additionally KLF 4 downregulates TNF a induced VCAM1 expression by targeting and blocking the binding site of NF kB to the VCAM1 promoter 101 However KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro inflammatory stimuli 59 KLF4 is essential for the cellular response to DNA damage It is required for preventing cell cycle entry into mitosis following g irradiation induced DNA damage 26 27 in promoting DNA repair mechanisms 20 and in preventing the irradiated cell from undergoing programmed cell death apoptosis 23 25 26 32 34 35 In one study the in vivo importance of KLF4 in response to g irradiation induced DNA damage was revealed where deletion of KLF4 specifically from the intestinal epithelium in mice lead to inability of the intestinal epithelium to regenerate and resulting in increased mortality of these mice 35 Importance in Stem cells editTakahashi and Yamanaka were the first to identify KLF4 as one of four factors oct 3 4 sox2 Klf4 c Myc that are required to induce mouse embryonic and adult fibroblasts into pluripotent stem cells iPS 23 This was also found to be true for adult human fibroblasts 22 Since 2006 up to today the work on clinically relevant research in stem cells and stem cell induction has increased dramatically more than 10 000 research articles as compared to about 60 between years 1900 to 2005 In vivo functional studies on the role of KLF4 in stem cells are rare Recently a group investigated the role of KLF4 in a particular population of intestinal stem cells the Bmi1 stem cells 37 This population of intestinal stem cells are normally slow dividing are known to be resistant to radiation injury and are the ones responsible for intestinal epithelium regeneration following radiation injury 102 The study showed that in the intestine following g irradiation induced DNA damage KLF4 may regulate epithelial regeneration by modulating the fate of Bmi1 BMI1 stem cells themselves and consequently the development of Bmi1 intestinal stem cell derived lineage 37 See also editKruppel like factorsNotes editThe 2017 version of this article was updated by an external expert under a dual publication model The corresponding academic peer reviewed article was published in Gene and can be cited as Amr M Ghaleb Vincent W Yang 22 February 2017 Kruppel like factor 4 KLF4 What we currently know Gene Gene Wiki Review Series 611 27 37 doi 10 1016 J GENE 2017 02 025 ISSN 0378 1119 PMC 5391259 PMID 28237823 Wikidata Q39151066 References edit a b c GRCh38 Ensembl release 89 ENSG00000136826 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000003032 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National 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23404342 Kumar M Allison DF Baranova NN Wamsley JJ Katz AJ Bekiranov S Jones DR Mayo MW 2013 NF kB regulates mesenchymal transition for the induction of non small cell lung cancer initiating cells PLOS ONE 8 7 e68597 Bibcode 2013PLoSO 868597K doi 10 1371 journal pone 0068597 PMC 3728367 PMID 23935876 Liu YN Abou Kheir W Yin JJ Fang L Hynes P Casey O Hu D Wan Y Seng V Sheppard Tillman H Martin P Kelly K March 2012 Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor b initiated prostate cancer epithelial mesenchymal transition Molecular and Cellular Biology 32 5 941 53 doi 10 1128 MCB 06306 11 PMC 3295188 PMID 22203039 Ouyang H Gore J Deitz S Korc M September 2014 microRNA 10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF b actions Oncogene 33 38 4664 74 doi 10 1038 onc 2013 405 PMC 3979498 PMID 24096486 Mistry DS Chen Y Wang Y Zhang K Sen GL December 2014 SNAI2 controls the undifferentiated state of human epidermal progenitor cells Stem Cells 32 12 3209 18 doi 10 1002 stem 1809 PMC 4339269 PMID 25100569 Liu S Yang H Chen Y He B Chen Q 2016 Kruppel Like Factor 4 Enhances Sensitivity of Cisplatin to Lung Cancer Cells and Inhibits Regulating Epithelial to Mesenchymal Transition Oncology Research 24 2 81 7 doi 10 3727 096504016X14597766487717 PMC 7838665 PMID 27296948 Zhang P Hong H Sun X Jiang H Ma S Zhao S Zhang M Wang Z Jiang C Liu H 15 January 2016 MicroRNA 10b regulates epithelial mesenchymal transition by modulating KLF4 Notch1 E cadherin in cisplatin resistant nasopharyngeal carcinoma cells American Journal of Cancer Research 6 2 141 56 PMC 4859649 PMID 27186392 Liao X Sharma N Kapadia F Zhou G Lu Y Hong H Paruchuri K Mahabeleshwar GH Dalmas E Venteclef N Flask CA Kim J Doreian BW Lu KQ Kaestner KH Hamik A Clement K Jain MK July 2011 Kruppel like factor 4 regulates macrophage polarization The Journal of Clinical Investigation 121 7 2736 49 doi 10 1172 JCI45444 PMC 3223832 PMID 21670502 Sharma N Lu Y Zhou G Liao X Kapil P Anand P Mahabeleshwar GH Stamler JS Jain MK December 2012 Myeloid Kruppel like factor 4 deficiency augments atherogenesis in ApoE mice brief report Arteriosclerosis Thrombosis and Vascular Biology 32 12 2836 8 doi 10 1161 ATVBAHA 112 300471 PMC 3574634 PMID 23065827 a b Stavri S Simionescu M Kardassis D Gafencu AV December 2015 Kruppel like factor 4 synergizes with CREB to increase the activity of apolipoprotein E gene promoter in macrophages Biochemical and Biophysical Research Communications 468 1 2 66 72 doi 10 1016 j bbrc 2015 10 163 PMID 26546821 Hale AT Longenecker CT Jiang Y Debanne SM Labatto DE Storer N Hamik A McComsey GA August 2015 HIV vasculopathy role of mononuclear cell associated Kruppel like factors 2 and 4 AIDS 29 13 1643 50 doi 10 1097 QAD 0000000000000756 PMC 4571286 PMID 26372274 Hale AT Tian H Anih E Recio FO Shatat MA Johnson T Liao X Ramirez Bergeron DL Proweller A Ishikawa M Hamik A April 2014 Endothelial Kruppel like factor 4 regulates angiogenesis and the Notch signaling pathway The Journal of Biological Chemistry 289 17 12016 28 doi 10 1074 jbc M113 530956 PMC 4002108 PMID 24599951 Cuttano R Rudini N Bravi L Corada M Giampietro C Papa E Morini MF Maddaluno L Baeyens N Adams RH Jain MK Owens GK Schwartz M Lampugnani MG Dejana E November 2015 KLF4 is a key determinant in the development and progression of cerebral cavernous malformations EMBO Molecular Medicine 8 1 6 24 doi 10 15252 emmm 201505433 PMC 4718159 PMID 26612856 Ghaleb AM Laroui H Merlin D Yang VW May 2014 Genetic deletion of Klf4 in the mouse intestinal epithelium ameliorates dextran sodium sulfate induced colitis by modulating the NF kB pathway inflammatory response Inflammatory Bowel Diseases 20 5 811 820 doi 10 1097 MIB 0000000000000022 PMC 4091934 PMID 24681655 Santoyo Suarez MG Mares Montemayor JD Padilla Rivas GR Delgado Gallegos JL Quiroz Reyes AG Roacho Perez JA et al February 2023 The Involvement of Kruppel like Factors in Cardiovascular Diseases Life 13 2 420 Bibcode 2023Life 13 420S doi 10 3390 life13020420 PMC 9962890 PMID 36836777 Yan KS Chia LA Li X Ootani A Su J Lee JY Su N Luo Y Heilshorn SC Amieva MR Sangiorgi E Capecchi MR Kuo CJ January 2012 The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations Proceedings of the National Academy of Sciences of the United States of America 109 2 466 71 Bibcode 2012PNAS 109 466Y doi 10 1073 pnas 1118857109 PMC 3258636 PMID 22190486 Further reading editRowland BD Peeper DS January 2006 KLF4 p21 and context dependent opposing forces in cancer Nature Reviews Cancer 6 1 11 23 doi 10 1038 nrc1780 PMID 16372018 S2CID 41981721 Shields JM Christy RJ Yang VW August 1996 Identification and characterization of a gene encoding a gut enriched Kruppel like factor expressed during growth arrest The Journal of Biological Chemistry 271 33 20009 17 doi 10 1074 jbc 271 33 20009 PMC 2330254 PMID 8702718 Garrett Sinha LA Eberspaecher H Seldin MF de Crombrugghe B December 1996 A gene for a novel zinc finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells The Journal of Biological Chemistry 271 49 31384 90 doi 10 1074 jbc 271 49 31384 PMID 8940147 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 January 1998 Human EZF a Kruppel like zinc finger protein is expressed in vascular endothelial cells and contains transcriptional activation and repression domains The Journal of Biological Chemistry 273 2 1026 31 doi 10 1074 jbc 273 2 1026 PMID 9422764 Zhang W Shields JM Sogawa K Fujii Kuriyama Y Yang VW July 1998 The gut enriched Kruppel like factor suppresses the activity of the CYP1A1 promoter in an Sp1 dependent fashion The Journal of Biological Chemistry 273 28 17917 25 doi 10 1074 jbc 273 28 17917 PMC 2275057 PMID 9651398 Foster KW Ren S Louro ID Lobo Ruppert SM McKie Bell P Grizzle W Hayes MR Broker TR Chow LT Ruppert JM June 1999 Oncogene expression cloning by retroviral transduction of adenovirus E1A immortalized rat kidney RK3E cells transformation of a host with epithelial features by c MYC and the zinc finger protein GKLF Cell Growth amp Differentiation 10 6 423 34 PMID 10392904 Segre JA Bauer C Fuchs E August 1999 Klf4 is a transcription factor required for establishing the barrier function of the skin Nature Genetics 22 4 356 60 doi 10 1038 11926 PMID 10431239 S2CID 3014700 Geiman DE Ton That H Johnson JM Yang VW March 2000 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 Research 28 5 1106 13 doi 10 1093 nar 28 5 1106 PMC 102607 PMID 10666450 Zhang W Geiman DE Shields JM Dang DT Mahatan CS Kaestner KH Biggs JR Kraft AS Yang VW June 2000 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 275 24 18391 8 doi 10 1074 jbc C000062200 PMC 2231805 PMID 10749849 Okano J Opitz OG Nakagawa H Jenkins TD Friedman SL Rustgi AK May 2000 The Kruppel like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact FEBS Letters 473 1 95 100 doi 10 1016 S0014 5793 00 01468 X PMID 10802067 S2CID 34923598 Higaki Y Schullery D Kawata Y Shnyreva M Abrass C Bomsztyk K June 2002 Synergistic activation of the rat laminin gamma1 chain promoter by the gut enriched Kruppel like factor GKLF KLF4 and Sp1 Nucleic Acids Research 30 11 2270 9 doi 10 1093 nar 30 11 2270 PMC 117209 PMID 12034813 Chen ZY Shie JL Tseng CC November 2002 Gut enriched Kruppel like factor represses ornithine decarboxylase gene expression and functions as checkpoint regulator in colonic cancer cells The Journal of Biological Chemistry 277 48 46831 9 doi 10 1074 jbc M204816200 PMID 12297499 Yoon HS Chen X Yang VW January 2003 Kruppel like factor 4 mediates p53 dependent G1 S cell cycle arrest in response to DNA damage The Journal of Biological Chemistry 278 4 2101 5 doi 10 1074 jbc M211027200 PMC 2229830 PMID 12427745 Wang N Liu ZH Ding F Wang XQ Zhou CN Wu M December 2002 Down regulation of gut enriched Kruppel like factor expression in esophageal cancer World Journal of Gastroenterology 8 6 966 70 doi 10 3748 wjg v8 i6 966 PMC 4656400 PMID 12439907 Chen X Whitney EM Gao SY Yang VW February 2003 Transcriptional profiling of Kruppel like factor 4 reveals a function in cell cycle regulation and epithelial differentiation Journal of Molecular Biology 326 3 665 77 doi 10 1016 S0022 2836 02 01449 3 PMC 2693487 PMID 12581631 Dang DT Chen X Feng J Torbenson M Dang LH Yang VW May 2003 Overexpression of Kruppel like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity Oncogene 22 22 3424 30 doi 10 1038 sj onc 1206413 PMC 2275074 PMID 12776194 Mao Z Song S Zhu Y Yi X Zhang H Shang Y Tong T July 2003 Transcriptional regulation of A33 antigen expression by gut enriched Kruppel like factor Oncogene 22 28 4434 43 doi 10 1038 sj onc 1206508 PMID 12853980 Ohnishi S Ohnami S Laub F Aoki K Suzuki K Kanai Y Haga K Asaka M Ramirez F Yoshida T August 2003 Downregulation and growth inhibitory effect of epithelial type Kruppel like transcription factor KLF4 but not KLF5 in bladder cancer Biochemical and Biophysical Research Communications 308 2 251 6 doi 10 1016 S0006 291X 03 01356 1 PMID 12901861 Hinnebusch BF Siddique A Henderson JW Malo MS Zhang W Athaide CP Abedrapo MA Chen X Yang VW Hodin RA January 2004 Enterocyte differentiation marker intestinal alkaline phosphatase is a target gene of the gut enriched Kruppel like factor American Journal of Physiology Gastrointestinal and Liver Physiology 286 1 G23 30 doi 10 1152 ajpgi 00203 2003 PMID 12919939 External links editKLF4 protein human at the U S National Library of Medicine Medical Subject Headings MeSH KLF4 microarray expression results and literature This article incorporates text from the United States National Library of Medicine which is in the public domain Retrieved from https en wikipedia org w index php title KLF4 amp oldid 1178759165, wikipedia, wiki, book, books, library,

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