Biology:KLF4

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2][3] 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.[4] It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2.[2] It has two nuclear localization sequences that signals it to localize to the nucleus.[5] 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.[6] The KLF4 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.[7] KLF4 was first identified in 1996.[8]

Interactions

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

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.[8][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

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.[citation needed]

KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization[90] and plaque formation in atherosclerosis.[91][92][93] It up-regulates Apolipoprotein E, which is an anti-atherosclerotic factor.[92] It is also involved in the regulation of angiogenesis. It may suppress angiogenesis by regulating NOTCH1 activity,[94] while in the central nervous system its overexpression leads to vascular dysplasia.[95]

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.[96] Additionally, KLF-4 downregulates TNF-α-induced VCAM1 expression by targeting and blocking the binding site of NF-κB to the VCAM1 promoter.[97]

However, KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro-inflammatory stimuli.[55]

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

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).[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.[98] 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.[33]

See also

Notes

References

  1. ↑ "Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer". Journal of Cellular Physiology 188 (2): 143–60. August 2001. doi:10.1002/jcp.1111. PMID 11424081. 
  2. ↑ 2.0 2.1 "The biology of the mammalian Krüppel-like family of transcription factors". The International Journal of Biochemistry & Cell Biology 32 (11–12): 1103–21. November 2000. doi:10.1016/s1357-2725(00)00059-5. PMID 11137451. 
  3. ↑ "Sp1- and Krüppel-like transcription factors". Genome Biology 4 (2): 206. 2003. doi:10.1186/gb-2003-4-2-206. PMID 12620113. 
  4. ↑ "Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts". Molecular Cancer 12: 89. August 2013. doi:10.1186/1476-4598-12-89. PMID 23919723. 
  5. ↑ "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. July 1997. doi:10.1074/jbc.272.29.18504. PMID 9218496. 
  6. ↑ "Entrez Gene: KLF4 Kruppel-like factor 4 (gut)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9314. 
  7. ↑ "Kruppel-like factor 4". https://www.ncbi.nlm.nih.gov/gene/9314. 
  8. ↑ 8.0 8.1 "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. August 1996. doi:10.1074/jbc.271.33.20009. PMID 8702718. 
  9. ↑ "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. December 1996. doi:10.1074/jbc.271.49.31384. PMID 8940147. 
  10. ↑ "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. March 2000. doi:10.1093/nar/28.5.1106. PMID 10666450. 
  11. ↑ "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. November 2007. doi:10.1074/jbc.M701847200. PMID 17908689. 
  12. ↑ "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. July 1998. doi:10.1074/jbc.273.28.17917. PMID 9651398. 
  13. ↑ "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. March 2004. doi:10.1074/jbc.M308278200. PMID 14670968. 
  14. ↑ 14.0 14.1 "Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages". The Journal of Biological Chemistry 280 (46): 38247–58. November 2005. doi:10.1074/jbc.M509378200. PMID 16169848. 
  15. ↑ "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. November 2006. doi:10.1158/1078-0432.CCR-06-1034. PMID 17085651. 
  16. ↑ "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. March 2000. doi:10.1093/nar/28.5.1106. PMID 10666450. 
  17. ↑ "Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells". Science 336 (6088): 1549–54. June 2012. doi:10.1126/science.1218370. PMID 22723415. Bibcode: 2012Sci...336.1549H. 
  18. ↑ 18.0 18.1 "Induction of pluripotent stem cells from adult human fibroblasts by defined factors". Cell 131 (5): 861–72. November 2007. doi:10.1016/j.cell.2007.11.019. PMID 18035408. 
  19. ↑ 19.0 19.1 "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell 126 (4): 663–76. August 2006. doi:10.1016/j.cell.2006.07.024. PMID 16904174. 
  20. ↑ 20.0 20.1 "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. August 2001. doi:10.1074/jbc.M101194200. PMID 11390382. 
  21. ↑ "Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity". Oncogene 22 (22): 3424–30. May 2003. doi:10.1038/sj.onc.1206413. PMID 12776194. 
  22. ↑ 22.0 22.1 22.2 "Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage". The Journal of Biological Chemistry 279 (6): 5035–41. February 2004. doi:10.1074/jbc.M307631200. PMID 14627709. 
  23. ↑ 23.0 23.1 23.2 "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. January 2003. doi:10.1074/jbc.M211027200. PMID 12427745. 
  24. ↑ "Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage". Oncogene 24 (25): 4017–25. June 2005. doi:10.1038/sj.onc.1208576. PMID 15806166. 
  25. ↑ "Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts". Molecular Cancer 12: 89. August 2013. doi:10.1186/1476-4598-12-89. PMID 23919723. 
  26. ↑ "Mouse embryonic fibroblasts null for the Krüppel-like factor 4 gene are genetically unstable". Oncogene 28 (9): 1197–205. March 2009. doi:10.1038/onc.2008.465. PMID 19137014. 
  27. ↑ "KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis". Molecular Cancer Research 14 (4): 385–96. April 2016. doi:10.1158/1541-7786.MCR-15-0410. PMID 26839262. 
  28. ↑ 28.0 28.1 "The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene". Nature Cell Biology 7 (11): 1074–82. November 2005. doi:10.1038/ncb1314. PMID 16244670. 
  29. ↑ 29.0 29.1 "KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells". Cancer Biology & Therapy 4 (11): 1216–21. November 2005. doi:10.4161/cbt.4.11.2090. PMID 16357509. 
  30. ↑ 30.0 30.1 "The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology". BioEssays 29 (6): 549–57. June 2007. doi:10.1002/bies.20581. PMID 17508399. 
  31. ↑ 31.0 31.1 31.2 "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. January 2015. doi:10.1152/ajpgi.00080.2014. PMID 25414097. 
  32. ↑ 32.0 32.1 32.2 "Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells". FEBS Open Bio 5: 147–54. 2 March 2015. doi:10.1016/j.fob.2015.02.003. PMID 25834779. 
  33. ↑ 33.0 33.1 33.2 "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. June 2016. doi:10.1016/j.stemcr.2016.04.014. PMID 27237377. 
  34. ↑ "[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. December 2007. PMID 18182717. 
  35. ↑ "KLF4 promotes hydrogen-peroxide-induced apoptosis of chronic myeloid leukemia cells involving the bcl-2/bax pathway". Cell Stress & Chaperones 15 (6): 905–12. November 2010. doi:10.1007/s12192-010-0199-5. PMID 20401760. 
  36. ↑ "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. January 2011. doi:10.1158/1940-6207.CAPR-10-0218. PMID 21205742. 
  37. ↑ "The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon". Development 129 (11): 2619–28. June 2002. doi:10.1242/dev.129.11.2619. PMID 12015290. 
  38. ↑ "Altered expression of the KLF4 in colorectal cancers". Pathology, Research and Practice 202 (8): 585–9. 2006. doi:10.1016/j.prp.2006.05.001. PMID 16814484. 
  39. ↑ "Haploinsufficiency of Krüppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis". Cancer Research 67 (15): 7147–54. August 2007. doi:10.1158/0008-5472.CAN-07-1302. PMID 17671182. 
  40. ↑ 40.0 40.1 "Altered intestinal epithelial homeostasis in mice with intestine-specific deletion of the Krüppel-like factor 4 gene". Developmental Biology 349 (2): 310–20. January 2011. doi:10.1016/j.ydbio.2010.11.001. PMID 21070761. 
  41. ↑ "Postnatal gene expression in the normal mouse cornea by SAGE". Investigative Ophthalmology & Visual Science 45 (2): 429–40. February 2004. doi:10.1167/iovs.03-0449. PMID 14744882. 
  42. ↑ "Regulation of corneal epithelial barrier function by Kruppel-like transcription factor 4". Investigative Ophthalmology & Visual Science 52 (3): 1762–9. March 2011. doi:10.1167/iovs.10-6134. PMID 21051695. 
  43. ↑ "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. August 2008. doi:10.1167/iovs.08-1811. PMID 18469187. 
  44. ↑ "Klf4 is a transcription factor required for establishing the barrier function of the skin". Nature Genetics 22 (4): 356–60. August 1999. doi:10.1038/11926. PMID 10431239. 
  45. ↑ "Ectopic expression of kruppel like factor 4 (Klf4) accelerates formation of the epidermal permeability barrier". Development 130 (12): 2767–77. June 2003. doi:10.1242/dev.00477. PMID 12736219. 
  46. ↑ "Deficiency of the Kruppel-like factor KLF4 correlates with increased cell proliferation and enhanced skin tumorigenesis". Carcinogenesis 33 (6): 1239–46. June 2012. doi:10.1093/carcin/bgs143. PMID 22491752. 
  47. ↑ "Krüppel-like factor 4 regulates membranous and endochondral ossification". Experimental Cell Research 318 (4): 311–25. February 2012. doi:10.1016/j.yexcr.2011.12.013. PMID 22206865. 
  48. ↑ "Kruppel-like factor 4 expression in osteoblasts represses osteoblast-dependent osteoclast maturation". Cell and Tissue Research 358 (1): 177–87. October 2014. doi:10.1007/s00441-014-1931-8. PMID 24927920. 
  49. ↑ "Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts". The Journal of Cell Biology 204 (6): 1063–74. March 2014. doi:10.1083/jcb.201308102. PMID 24616223. 
  50. ↑ "Spatial and temporal expression of KLF4 and KLF5 during murine tooth development". Archives of Oral Biology 54 (5): 403–11. May 2009. doi:10.1016/j.archoralbio.2009.02.003. PMID 19268913. 
  51. ↑ "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. April 2010. doi:10.1530/REP-09-0531. PMID 20051481. 
  52. ↑ "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. July 2002. doi:10.1016/s0925-4773(02)00127-2. PMID 12049784. 
  53. ↑ "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. February 2008. doi:10.1002/jcp.21201. PMID 17620326. 
  54. ↑ "Krüppel-like factor 4 is involved in functional differentiation of testicular Sertoli cells". Developmental Biology 315 (2): 552–66. March 2008. doi:10.1016/j.ydbio.2007.12.018. PMID 18243172. 
  55. ↑ 55.0 55.1 "Kruppel-like factor 4 regulates endothelial inflammation". The Journal of Biological Chemistry 282 (18): 13769–79. May 2007. doi:10.1074/jbc.M700078200. PMID 17339326. 
  56. ↑ "Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function". Circulation Research 107 (8): 959–66. October 2010. doi:10.1161/CIRCRESAHA.110.219592. PMID 20724706. 
  57. ↑ "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. 2005. doi:10.1016/j.bcmd.2005.04.009. PMID 16023392. 
  58. ↑ "KLF4 regulates the expression of interleukin-10 in RAW264.7 macrophages". Biochemical and Biophysical Research Communications 362 (3): 575–81. October 2007. doi:10.1016/j.bbrc.2007.07.157. PMID 17719562. 
  59. ↑ "The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation". The EMBO Journal 26 (18): 4138–48. September 2007. doi:10.1038/sj.emboj.7601824. PMID 17762869. 
  60. ↑ 60.0 60.1 "Krüppel-like factor 4 regulates B cell number and activation-induced B cell proliferation". Journal of Immunology 179 (7): 4679–84. October 2007. doi:10.4049/jimmunol.179.7.4679. PMID 17878366. 
  61. ↑ "KLF4 is a FOXO target gene that suppresses B cell proliferation". International Immunology 20 (5): 671–81. May 2008. doi:10.1093/intimm/dxn024. PMID 18375530. 
  62. ↑ "Generation of induced pluripotent stem cells from human kidney mesangial cells". Journal of the American Society of Nephrology 22 (7): 1213–20. July 2011. doi:10.1681/ASN.2010101022. PMID 21566060. 
  63. ↑ "Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria". Kidney International 88 (4): 745–53. October 2015. doi:10.1038/ki.2015.178. PMID 26108068. 
  64. ↑ "The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells". Clinical and Experimental Pharmacology & Physiology 42 (6): 680–6. June 2015. doi:10.1111/1440-1681.12405. PMID 25882815. 
  65. ↑ "Matrix-Stiffness-Regulated Inverse Expression of Krüppel-Like Factor 5 and Krüppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis". The American Journal of Pathology 185 (9): 2468–81. September 2015. doi:10.1016/j.ajpath.2015.05.019. PMID 26212907. 
  66. ↑ "Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer". Oncogene 23 (2): 395–402. January 2004. doi:10.1038/sj.onc.1207067. PMID 14724568. 
  67. ↑ "Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression". Cancer Research 65 (7): 2746–54. April 2005. doi:10.1158/0008-5472.CAN-04-3619. PMID 15805274. 
  68. ↑ "Expression of the gut-enriched Krüppel-like factor gene during development and intestinal tumorigenesis". FEBS Letters 419 (2–3): 239–43. December 1997. doi:10.1016/s0014-5793(97)01465-8. PMID 9428642. 
  69. ↑ "Epigenetics of prostate cancer: beyond DNA methylation". Journal of Cellular and Molecular Medicine 10 (1): 100–25. January 2006. doi:10.1111/j.1582-4934.2006.tb00293.x. PMID 16563224. 
  70. ↑ "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. August 2003. doi:10.1016/s0006-291x(03)01356-1. PMID 12901861. 
  71. ↑ "Putative tumor-suppressive function of Kruppel-like factor 4 in primary lung carcinoma". Clinical Cancer Research 15 (18): 5688–95. September 2009. doi:10.1158/1078-0432.CCR-09-0310. PMID 19737957. 
  72. ↑ "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. June 1999. PMID 10392904. 
  73. ↑ "Increase of GKLF messenger RNA and protein expression during progression of breast cancer". Cancer Research 60 (22): 6488–95. November 2000. PMID 11103818. 
  74. ↑ "Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia". Oncogene 24 (9): 1491–500. February 2005. doi:10.1038/sj.onc.1208307. PMID 15674344. 
  75. ↑ "KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia". Cancer Biology & Therapy 4 (12): 1401–8. December 2005. doi:10.4161/cbt.4.12.2355. PMID 16357510. 
  76. ↑ 76.0 76.1 "Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice". Gastroenterology 139 (6): 2124–2134.e9. December 2010. doi:10.1053/j.gastro.2010.08.048. PMID 20816834. 
  77. ↑ "p53-dependent regulation of growth, epithelial-mesenchymal transition and stemness in normal pancreatic epithelial cells". Cell Cycle 10 (8): 1312–21. April 2011. doi:10.4161/cc.10.8.15363. PMID 21490434. 
  78. ↑ "DCLK1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms in pancreatic cancer". PLOS ONE 8 (9): e73940. 9 September 2013. doi:10.1371/journal.pone.0073940. PMID 24040120. Bibcode: 2013PLoSO...873940S. 
  79. ↑ "The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs". Nature Cell Biology 11 (12): 1487–95. December 2009. doi:10.1038/ncb1998. PMID 19935649. 
  80. ↑ "Doxycycline inducible Krüppel-like factor 4 lentiviral vector mediates mesenchymal to epithelial transition in ovarian cancer cells". PLOS ONE 9 (8): e105331. 19 August 2014. doi:10.1371/journal.pone.0105331. PMID 25137052. Bibcode: 2014PLoSO...9j5331C. 
  81. ↑ "MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1". Molecular Cancer 10: 99. August 2011. doi:10.1186/1476-4598-10-99. PMID 21851624. 
  82. ↑ "Aldehyde dehydrogenase 1, a functional marker for identifying cancer stem cells in human nasopharyngeal carcinoma". Cancer Letters 330 (2): 181–9. April 2013. doi:10.1016/j.canlet.2012.11.046. PMID 23220285. 
  83. ↑ "Wild-type p53 suppresses the epithelial-mesenchymal transition and stemness in PC-3 prostate cancer cells by modulating miR‑145". International Journal of Oncology 42 (4): 1473–81. April 2013. doi:10.3892/ijo.2013.1825. PMID 23404342. 
  84. ↑ "NF-κB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells". PLOS ONE 8 (7): e68597. 2013. doi:10.1371/journal.pone.0068597. PMID 23935876. Bibcode: 2013PLoSO...868597K. 
  85. ↑ "Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition". Molecular and Cellular Biology 32 (5): 941–53. March 2012. doi:10.1128/MCB.06306-11. PMID 22203039. 
  86. ↑ "microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions". Oncogene 33 (38): 4664–74. September 2014. doi:10.1038/onc.2013.405. PMID 24096486. 
  87. ↑ "SNAI2 controls the undifferentiated state of human epidermal progenitor cells". Stem Cells 32 (12): 3209–18. December 2014. doi:10.1002/stem.1809. PMID 25100569. 
  88. ↑ "Krüppel-Like Factor 4 Enhances Sensitivity of Cisplatin to Lung Cancer Cells and Inhibits Regulating Epithelial-to-Mesenchymal Transition". Oncology Research 24 (2): 81–7. 2016. doi:10.3727/096504016X14597766487717. PMID 27296948. 
  89. ↑ "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. 15 January 2016. PMID 27186392. 
  90. ↑ "Krüppel-like factor 4 regulates macrophage polarization". The Journal of Clinical Investigation 121 (7): 2736–49. July 2011. doi:10.1172/JCI45444. PMID 21670502. 
  91. ↑ "Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report". Arteriosclerosis, Thrombosis, and Vascular Biology 32 (12): 2836–8. December 2012. doi:10.1161/ATVBAHA.112.300471. PMID 23065827. 
  92. ↑ 92.0 92.1 "Krüppel-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. December 2015. doi:10.1016/j.bbrc.2015.10.163. PMID 26546821. 
  93. ↑ "HIV vasculopathy: role of mononuclear cell-associated Krüppel-like factors 2 and 4". AIDS 29 (13): 1643–50. August 2015. doi:10.1097/QAD.0000000000000756. PMID 26372274. 
  94. ↑ "Endothelial Kruppel-like factor 4 regulates angiogenesis and the Notch signaling pathway". The Journal of Biological Chemistry 289 (17): 12016–28. April 2014. doi:10.1074/jbc.M113.530956. PMID 24599951. 
  95. ↑ "KLF4 is a key determinant in the development and progression of cerebral cavernous malformations". EMBO Molecular Medicine 8 (1): 6–24. November 2015. doi:10.15252/emmm.201505433. PMID 26612856. 
  96. ↑ "Genetic deletion of Klf4 in the mouse intestinal epithelium ameliorates dextran sodium sulfate-induced colitis by modulating the NF-κB pathway inflammatory response". Inflammatory Bowel Diseases 20 (5): 811–820. May 2014. doi:10.1097/MIB.0000000000000022. PMID 24681655. 
  97. ↑ "The Involvement of Krüppel-like Factors in Cardiovascular Diseases". Life 13 (2): 420. February 2023. doi:10.3390/life13020420. PMID 36836777. Bibcode: 2023Life...13..420S. 
  98. ↑ "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. January 2012. doi:10.1073/pnas.1118857109. PMID 22190486. Bibcode: 2012PNAS..109..466Y. 

Further reading

External links

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



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:KLF4&oldid=3588347"