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KLF4

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Kruppel-like factor 4 (KLF4; gut-enriched Krüppel-like factor or GKLF) is a zinc-finger transcription factor, and it was first identified in 1996.[1] KLF4 is a member of the KLF family of transcription factors, which belongs to the relatively large family of SP1-like transcription factors.[2][3][4] 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.[5] It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2.[3] It has two nuclear localization sequences that signals it to localize to the nucleus.[6] 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).

In humans, the protein is 513 amino acids with a predicted molecular weight of approximately 55kDa and is encoded by the KLF4 gene.[7] The KLF4 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.[8]

Interactions[edit | edit source]

KLF4 can activate transcription by interacting via it N-terminus with specific transcriptional co-activators, such as p300-CBP coactivator family.[9][10][11] Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence (9-12).[12][13][14][15] KLF4 has been shown to interact with CREB-binding protein.[16]

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.[17]

Function[edit | edit source]

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.[18][19] KLF4 is highly expressed in non-dividing cells and its overexpression induces cell cycle arrest.[1][20][21][22][23] KLF4 is particularly important in preventing cell division when the DNA is damaged.[20][22][23][24] KLF4 is also important in regulating centrosome number and chromosome number (genetic stability),[25][26][27] and in promoting cell survival.[28][29][30][31][32][33] However, some studies have revealed that under certain conditions KLF4 may switch its role from pro-cell survival to pro-cell death.[32][34][35][36]

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).[37][38][39][40] In the intestinal epithelium, KLF4 is an important regulator of Wnt signaling pathway genes of genes regulating differentiation.[40]

KLF4 is expressed in a variety of tissues and organs such as: the cornea where it is required for epithelial barrier function[41][42] and is a regulator of genes required for corneal homeostasis;[43] the skin where it is required for the development of skin permeability barrier function;[44][45][46] the bone and teeth tissues where it regulates normal skeletal development;[47][48][49][50] epithelial cell of the mouse male and female reproductive tract[51] where in the males it is important for proper spermatogenesis;[52][53][54] vascular endothelial cells[55] where it is critical in preventing vascular leakage in response to inflammatory stimuli;[56] white blood cells where it mediates inflammatory responses cellular differentiation[57][58][59][60] and proliferation;[60][61] the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem (iPS) cells to renal lineage in vitro[62] and its dysregulation has been linked to some renal pathologies.[63][64][65]

Roles in diseases[edit | edit source]

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,[66] gastric cancer,[67] esophageal squamous cell carcinoma,[29] intestinal cancer,[68] prostate cancer,[69] bladder cancer[70] and lung cancer.[71]

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[72] and in primary breast ductal carcinoma.[73] Also, overexpression of KLF4 in skin resulted in hyperplasia and dysplasia,[74] which lead to the development of squamous cell carcinoma.[75] 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.[76]

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,[77][78][79] head and neck cancer,[80] endometrial cancer,[81] nasopharyngeal cancer,[82] prostate cancer[83] and non-small lung cancer.[84] 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[85] and pancreatic cancer.[86] Additionally, KLF4 was shown to suppress EMT in epidermal cancer,[87] breast cancer,[32] lung cancer,[88] cisplatin-resistant nasopharyngeal carcinoma cells,[89] and in hepatocellular carcinoma cells.[90]

KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization[91] and plaque formation in atherosclerosis.[92][93][94] It up-regulates Apolipoprotein E, which is an anti-atherosclerotic factor.[93] It is also involved in the regulation of angiogenesis. It may suppress angiogenesis by regulating NOTCH1 activity,[95] while in the central nervous system its overexpression leads to vascular dysplasia.[96]

KLF4 may promote inflammation by mediating NF-κB-dependent inflammatory pathway such as in macrophages,[14] esophageal epithelium[76] and in chemically-induced acute colitis in mice.[97] However, KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro-inflammatory stimuli.[98]

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,[22][23] in promoting DNA repair mechanisms (20) and in preventing the irradiated cell from undergoing programmed cell death (apoptosis) (23,25,26).[28][30][31] 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.[31]

Importance in Stem cells[edit | edit source]

Takahashi and Yamanaka were the first identify KLF4 as one of four factors that are required to induce mouse embryonic and adult fibroblasts into pluripotent stem cells (iPS).[19] This was also found to be true for adult human fibroblasts.[18] 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.[33] 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.[99] The study showed that in the intestine, following γ-irradiation-induced DNA damage, KLF4 may regulate epithelial regeneration by modulating the fate of Bmi1+ stem cells themselves, and consequently the development of BMI1+ intestinal stem cell-derived lineage.[33]

See also[edit | edit source]

Notes[edit | edit source]


References[edit | edit source]

  1. ↑ 1.0 1.1 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.
  2. ↑ Black AR, Black JD, Azizkhan-Clifford J (August 2001). "Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer". Journal of Cellular Physiology. 188 (2): 143–60. doi:10.1002/jcp.1111. PMID 11424081.
  3. ↑ 3.0 3.1 Dang DT, Pevsner J, Yang VW (November 2000). "The biology of the mammalian Krüppel-like family of transcription factors". The International Journal of Biochemistry & Cell Biology. 32 (11–12): 1103–21. doi:10.1016/s1357-2725(00)00059-5. PMC 2754176. PMID 11137451.
  4. ↑ Kaczynski J, Cook T, Urrutia R (2003). "Sp1- and Krüppel-like transcription factors". Genome Biology. 4 (2): 206. doi:10.1186/gb-2003-4-2-206. PMC 151296. PMID 12620113.
  5. ↑ El-Karim EA, Hagos EG, Ghaleb AM, Yu B, Yang VW (August 2013). "Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts". Molecular Cancer. 12: 89. doi:10.1186/1476-4598-12-89. PMC 3750599. PMID 23919723.
  6. ↑ Shields JM, Yang VW (July 1997). "Two potent nuclear localization signals in the gut-enriched Krüppel-like factor define a subfamily of closely related Krüppel proteins". The Journal of Biological Chemistry. 272 (29): 18504–7. doi:10.1074/jbc.272.29.18504. PMC 2268085. PMID 9218496.
  7. ↑ "Entrez Gene: KLF4 Kruppel-like factor 4 (gut)".
  8. ↑ "Kruppel-like factor 4".
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Evans PM, Zhang W, Chen X, Yang J, Bhakat KK, Liu C (November 2007). "Kruppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation". The Journal of Biological Chemistry. 282 (47): 33994–4002. doi:10.1074/jbc.M701847200. PMID 17908689.
  12. ↑ 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.
  13. ↑ Ai W, Liu Y, Langlois M, Wang TC (March 2004). "Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements". The Journal of Biological Chemistry. 279 (10): 8684–93. doi:10.1074/jbc.M308278200. PMID 14670968.
  14. ↑ 14.0 14.1 Feinberg MW, Cao Z, Wara AK, Lebedeva MA, Senbanerjee S, Jain MK (November 2005). "Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages". The Journal of Biological Chemistry. 280 (46): 38247–58. doi:10.1074/jbc.M509378200. PMID 16169848.
  15. ↑ Kanai M, Wei D, Li Q, Jia Z, Ajani J, Le X, Yao J, Xie K (November 2006). "Loss of Krüppel-like factor 4 expression contributes to Sp1 overexpression and human gastric cancer development and progression". Clinical Cancer Research. 12 (21): 6395–402. doi:10.1158/1078-0432.CCR-06-1034. PMID 17085651.
  16. ↑ 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.
  17. ↑ Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R, Kemler R (June 2012). "Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells". Science. 336 (6088): 1549–54. doi:10.1126/science.1218370. PMID 22723415.
  18. ↑ 18.0 18.1 Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (November 2007). "Induction of pluripotent stem cells from adult human fibroblasts by defined factors". Cell. 131 (5): 861–72. doi:10.1016/j.cell.2007.11.019. PMID 18035408.
  19. ↑ 19.0 19.1 Takahashi K, Yamanaka S (August 2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
  20. ↑ 20.0 20.1 Chen X, Johns DC, Geiman DE, Marban E, Dang DT, Hamlin G, Sun R, Yang VW (August 2001). "Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle". The Journal of Biological Chemistry. 276 (32): 30423–8. doi:10.1074/jbc.M101194200. PMC 2330258. PMID 11390382.
  21. ↑ 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.
  22. ↑ 22.0 22.1 22.2 Yoon HS, Yang VW (February 2004). "Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage". The Journal of Biological Chemistry. 279 (6): 5035–41. doi:10.1074/jbc.M307631200. PMC 1262649. PMID 14627709.
  23. ↑ 23.0 23.1 23.2 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.
  24. ↑ Yoon HS, Ghaleb AM, Nandan MO, Hisamuddin IM, Dalton WB, Yang VW (June 2005). "Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage". Oncogene. 24 (25): 4017–25. doi:10.1038/sj.onc.1208576. PMC 1626272. PMID 15806166.
  25. ↑ El-Karim EA, Hagos EG, Ghaleb AM, Yu B, Yang VW (August 2013). "Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts". Molecular Cancer. 12: 89. doi:10.1186/1476-4598-12-89. PMC 3750599. PMID 23919723.
  26. ↑ Hagos EG, Ghaleb AM, Dalton WB, Bialkowska AB, Yang VW (March 2009). "Mouse embryonic fibroblasts null for the Krüppel-like factor 4 gene are genetically unstable". Oncogene. 28 (9): 1197–205. doi:10.1038/onc.2008.465. PMC 2667867. PMID 19137014.
  27. ↑ Ghaleb AM, Elkarim EA, Bialkowska AB, Yang VW (April 2016). "KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis". Molecular Cancer Research. 14 (4): 385–96. doi:10.1158/1541-7786.MCR-15-0410. PMC 4834227. PMID 26839262.
  28. ↑ 28.0 28.1 Rowland BD, Bernards R, Peeper DS (November 2005). "The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene". Nature Cell Biology. 7 (11): 1074–82. doi:10.1038/ncb1314. PMID 16244670.
  29. ↑ 29.0 29.1 Yang Y, Goldstein BG, Chao HH, Katz JP (November 2005). "KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells". Cancer Biology & Therapy. 4 (11): 1216–21. doi:10.4161/cbt.4.11.2090. PMID 16357509.
  30. ↑ 30.0 30.1 McConnell BB, Ghaleb AM, Nandan MO, Yang VW (June 2007). "The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology". BioEssays. 29 (6): 549–57. doi:10.1002/bies.20581. PMC 2211634. PMID 17508399.
  31. ↑ 31.0 31.1 31.2 Talmasov D, Xinjun Z, Yu B, Nandan MO, Bialkowska AB, Elkarim E, Kuruvilla J, Yang VW, Ghaleb AM (January 2015). "Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice". American Journal of Physiology. Gastrointestinal and Liver Physiology. 308 (2): G121–38. doi:10.1152/ajpgi.00080.2014. PMC 4297857. PMID 25414097.
  32. ↑ 32.0 32.1 32.2 Wang B, Zhao MZ, Cui NP, Lin DD, Zhang AY, Qin Y, Liu CY, Yan WT, Shi JH, Chen BP (2 March 2015). "Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells". FEBS Open Bio. 5: 147–54. doi:10.1016/j.fob.2015.02.003. PMC 4359971. PMID 25834779.
  33. ↑ 33.0 33.1 33.2 Kuruvilla JG, Kim CK, Ghaleb AM, Bialkowska AB, Kuo CJ, Yang VW (June 2016). "Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice". Stem Cell Reports. 6 (6): 815–24. doi:10.1016/j.stemcr.2016.04.014. PMC 4911500. PMID 27237377.
  34. ↑ Liu MD, Liu Y, Liu JW, Zhang HL, Xiao XZ (December 2007). "[Effect of Krüppel-like factor 4 overexpression on heat stress-induced apoptosis of Raw264.7 macrophages]". Zhong Nan Da Xue Xue Bao. Yi Xue Ban = Journal of Central South University. Medical Sciences. 32 (6): 1002–6. PMID 18182717.
  35. ↑ Li Z, Zhao J, Li Q, Yang W, Song Q, Li W, Liu J (November 2010). "KLF4 promotes hydrogen-peroxide-induced apoptosis of chronic myeloid leukemia cells involving the bcl-2/bax pathway". Cell Stress & Chaperones. 15 (6): 905–12. doi:10.1007/s12192-010-0199-5. PMC 3024064. PMID 20401760.
  36. ↑ Whitlock NC, Bahn JH, Lee SH, Eling TE, Baek SJ (January 2011). "Resveratrol-induced apoptosis is mediated by early growth response-1, Krüppel-like factor 4, and activating transcription factor 3". Cancer Prevention Research. 4 (1): 116–27. doi:10.1158/1940-6207.CAPR-10-0218. PMC 3064282. PMID 21205742.
  37. ↑ Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW, Kaestner KH (June 2002). "The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon". Development. 129 (11): 2619–28. PMC 2225535. PMID 12015290.
  38. ↑ Choi BJ, Cho YG, Song JW, Kim CJ, Kim SY, Nam SW, Yoo NJ, Lee JY, Park WS (2006). "Altered expression of the KLF4 in colorectal cancers". Pathology, Research and Practice. 202 (8): 585–9. doi:10.1016/j.prp.2006.05.001. PMID 16814484.
  39. ↑ Ghaleb AM, McConnell BB, Nandan MO, Katz JP, Kaestner KH, Yang VW (August 2007). "Haploinsufficiency of Krüppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis". Cancer Research. 67 (15): 7147–54. doi:10.1158/0008-5472.CAN-07-1302. PMC 2373271. PMID 17671182.
  40. ↑ 40.0 40.1 Ghaleb AM, McConnell BB, Kaestner KH, Yang VW (January 2011). "Altered intestinal epithelial homeostasis in mice with intestine-specific deletion of the Krüppel-like factor 4 gene". Developmental Biology. 349 (2): 310–20. doi:10.1016/j.ydbio.2010.11.001. PMC 3022386. PMID 21070761.
  41. ↑ Norman B, Davis J, Piatigorsky J (February 2004). "Postnatal gene expression in the normal mouse cornea by SAGE". Investigative Ophthalmology & Visual Science. 45 (2): 429–40. doi:10.1167/iovs.03-0449. PMID 14744882.
  42. ↑ Swamynathan S, Kenchegowda D, Piatigorsky J, Swamynathan S (March 2011). "Regulation of corneal epithelial barrier function by Kruppel-like transcription factor 4". Investigative Ophthalmology & Visual Science. 52 (3): 1762–9. doi:10.1167/iovs.10-6134. PMC 3101671. PMID 21051695.
  43. ↑ Swamynathan SK, Davis J, Piatigorsky J (August 2008). "Identification of candidate Klf4 target genes reveals the molecular basis of the diverse regulatory roles of Klf4 in the mouse cornea". Investigative Ophthalmology & Visual Science. 49 (8): 3360–70. doi:10.1167/iovs.08-1811. PMC 2774783. PMID 18469187.
  44. ↑ 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.
  45. ↑ Jaubert J, Cheng J, Segre JA (June 2003). "Ectopic expression of kruppel like factor 4 (Klf4) accelerates formation of the epidermal permeability barrier". Development. 130 (12): 2767–77. doi:10.1242/dev.00477. PMID 12736219.
  46. ↑ Li J, Zheng H, Yu F, Yu T, Liu C, Huang S, Wang TC, Ai W (June 2012). "Deficiency of the Kruppel-like factor KLF4 correlates with increased cell proliferation and enhanced skin tumorigenesis". Carcinogenesis. 33 (6): 1239–46. doi:10.1093/carcin/bgs143. PMC 3388492. PMID 22491752.
  47. ↑ Michikami I, Fukushi T, Tanaka M, Egusa H, Maeda Y, Ooshima T, Wakisaka S, Abe M (February 2012). "Krüppel-like factor 4 regulates membranous and endochondral ossification". Experimental Cell Research. 318 (4): 311–25. doi:10.1016/j.yexcr.2011.12.013. PMID 22206865.
  48. ↑ Fujikawa J, Tanaka M, Itoh S, Fukushi T, Kurisu K, Takeuchi Y, Morisaki I, Wakisaka S, Abe M (October 2014). "Kruppel-like factor 4 expression in osteoblasts represses osteoblast-dependent osteoclast maturation". Cell and Tissue Research. 358 (1): 177–87. doi:10.1007/s00441-014-1931-8. PMID 24927920.
  49. ↑ Kim JH, Kim K, Youn BU, Lee J, Kim I, Shin HI, Akiyama H, Choi Y, Kim N (March 2014). "Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts". The Journal of Cell Biology. 204 (6): 1063–74. doi:10.1083/jcb.201308102. PMC 3998795. PMID 24616223.
  50. ↑ Chen Z, Couble ML, Mouterfi N, Magloire H, Chen Z, Bleicher F (May 2009). "Spatial and temporal expression of KLF4 and KLF5 during murine tooth development". Archives of Oral Biology. 54 (5): 403–11. doi:10.1016/j.archoralbio.2009.02.003. PMID 19268913.
  51. ↑ Godmann M, Kosan C, Behr R (April 2010). "Krüppel-like factor 4 is widely expressed in the mouse male and female reproductive tract and responds as an immediate early gene to activation of the protein kinase A in TM4 Sertoli cells". Reproduction. 139 (4): 771–82. doi:10.1530/REP-09-0531. PMID 20051481.
  52. ↑ Behr R, Kaestner KH (July 2002). "Developmental and cell type-specific expression of the zinc finger transcription factor Krüppel-like factor 4 (Klf4) in postnatal mouse testis". Mechanisms of Development. 115 (1–2): 167–9. doi:10.1016/s0925-4773(02)00127-2. PMID 12049784.
  53. ↑ Sze KL, Lee WM, Lui WY (February 2008). "Expression of CLMP, a novel tight junction protein, is mediated via the interaction of GATA with the Kruppel family proteins, KLF4 and Sp1, in mouse TM4 Sertoli cells". Journal of Cellular Physiology. 214 (2): 334–44. doi:10.1002/jcp.21201. PMID 17620326.
  54. ↑ Godmann M, Katz JP, Guillou F, Simoni M, Kaestner KH, Behr R (March 2008). "Krüppel-like factor 4 is involved in functional differentiation of testicular Sertoli cells". Developmental Biology. 315 (2): 552–66. doi:10.1016/j.ydbio.2007.12.018. PMC 2292099. PMID 18243172.
  55. ↑ Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK (May 2007). "Kruppel-like factor 4 regulates endothelial inflammation". The Journal of Biological Chemistry. 282 (18): 13769–79. doi:10.1074/jbc.M700078200. PMID 17339326.
  56. ↑ Cowan CE, Kohler EE, Dugan TA, Mirza MK, Malik AB, Wary KK (October 2010). "Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function". Circulation Research. 107 (8): 959–66. doi:10.1161/CIRCRESAHA.110.219592. PMC 3018700. PMID 20724706.
  57. ↑ Zhang P, Basu P, Redmond LC, Morris PE, Rupon JW, Ginder GD, Lloyd JA (2005). "A functional screen for Krüppel-like factors that regulate the human gamma-globin gene through the CACCC promoter element". Blood Cells, Molecules & Diseases. 35 (2): 227–35. doi:10.1016/j.bcmd.2005.04.009. PMID 16023392.
  58. ↑ Liu J, Zhang H, Liu Y, Wang K, Feng Y, Liu M, Xiao X (October 2007). "KLF4 regulates the expression of interleukin-10 in RAW264.7 macrophages". Biochemical and Biophysical Research Communications. 362 (3): 575–81. doi:10.1016/j.bbrc.2007.07.157. PMID 17719562.
  59. ↑ Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H, Hirai H, Katz JP, Haspel RL, Gray S, Akashi K, Segre J, Kaestner KH, Tenen DG, Jain MK (September 2007). "The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation". The EMBO Journal. 26 (18): 4138–48. doi:10.1038/sj.emboj.7601824. PMC 2230668. PMID 17762869.
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