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Gene Review

KLF2  -  Kruppel-like factor 2

Homo sapiens

Synonyms: Krueppel-like factor 2, LKLF, Lung krueppel-like factor
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Disease relevance of KLF2

  • Utilizing gene expression profiling to identify aberrantly expressed genes in ovarian cancer, we found that KLF2 was significantly and specifically downregulated in ovarian tumors [1].
  • KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis [2].
  • Overexpression and silencing of KLF2 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KLF2 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development [2].
  • Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation [3].
  • A study of the relationships between KLF2 polymorphisms and body weight control in a French population [4].

High impact information on KLF2

  • Conversely, LKLF-deficient peripheral T cells produced by gene targeting showed increased proliferation, increased cell size and enhanced expression of surface activation markers in vivo [5].
  • LKLF appeared to function, at least in part, by decreasing expression of the proto-oncogene encoding c-Myc [5].
  • Here we show that forced expression of the lung Krüppel-like transcription factor (LKLF) in Jurkat T cells is sufficient to program a quiescent phenotype characterized by decreased proliferation, reduced cell size and protein synthesis and decreased surface expression of activation markers [5].
  • Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity [6].
  • In addition, KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines [6].

Biological context of KLF2

  • KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo [7].
  • Both activation and zinc-finger domains of KLF2 were required for this suppression of Wee1 expression [1].
  • Thus, the level of WEE1 is regulated by KLF2 and enhanced KLF2 expression sensitizes cells to DNA damage-induced apoptosis [1].
  • After reintroducing KLF2 into ovarian cancer cell lines, we observed decreased cell growth and increased sensitivity to DNA damage-induced apoptosis [1].
  • In addition, we demonstrated that Wee1 expression prevents cancer cells from undergoing apoptosis in response to DNA damage; however, this resistance was abolished by coexpression of KLF2, which inhibits WEE1 transcription [1].

Anatomical context of KLF2


Associations of KLF2 with chemical compounds


Physical interactions of KLF2

  • Here, we demonstrate that WWP1 interacts with KLF2 in vivo and mediates both poly-ubiquitination and proteasomal degradation of KLF2 [15].

Regulatory relationships of KLF2

  • In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic epsilon-globin gene but not the adult beta-globin gene, suggesting that this developmental-stage-specific role is evolutionarily conserved [7].
  • Our experiments demonstrate for the first time that WWP1 promotes ubiquitination and degradation of KLF2 and is not involved in the ubiquitin-transfer reaction [15].
  • Tumor necrosis factor alpha (TNF-alpha) potently inhibited KLF2 expression [12].
  • Mechanistically, KLF2 inhibits PAR-1 expression and, as a consequence, thrombin-mediated nuclear factor kappaB (NF-kappaB) nuclear accumulation and DNA binding [16].
  • Inhibition of either PI3K or AKT and depletion of AKT abrogated Ang1-induced KLF2 expression [17].

Other interactions of KLF2


Analytical, diagnostic and therapeutic context of KLF2


  1. Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis. Wang, F., Zhu, Y., Huang, Y., McAvoy, S., Johnson, W.B., Cheung, T.H., Chung, T.K., Lo, K.W., Yim, S.F., Yu, M.M., Ngan, H.Y., Wong, Y.F., Smith, D.I. Oncogene (2005) [Pubmed]
  2. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. Parmar, K.M., Larman, H.B., Dai, G., Zhang, Y., Wang, E.T., Moorthy, S.N., Kratz, J.R., Lin, Z., Jain, M.K., Gimbrone, M.A., García-Cardeña, G. J. Clin. Invest. (2006) [Pubmed]
  3. Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Das, H., Kumar, A., Lin, Z., Patino, W.D., Hwang, P.M., Feinberg, M.W., Majumder, P.K., Jain, M.K. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  4. A study of the relationships between KLF2 polymorphisms and body weight control in a French population. Meirhaeghe, A., Cottel, D., Amouyel, P. BMC Med. Genet. (2006) [Pubmed]
  5. Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc--dependent pathway. Buckley, A.F., Kuo, C.T., Leiden, J.M. Nat. Immunol. (2001) [Pubmed]
  6. KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. SenBanerjee, S., Lin, Z., Atkins, G.B., Greif, D.M., Rao, R.M., Kumar, A., Feinberg, M.W., Chen, Z., Simon, D.I., Luscinskas, F.W., Michel, T.M., Gimbrone, M.A., García-Cardeña, G., Jain, M.K. J. Exp. Med. (2004) [Pubmed]
  7. KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo. Basu, P., Morris, P.E., Haar, J.L., Wani, M.A., Lingrel, J.B., Gaensler, K.M., Lloyd, J.A. Blood (2005) [Pubmed]
  8. A functional screen for Krüppel-like factors that regulate the human gamma-globin gene through the CACCC promoter element. Zhang, P., Basu, P., Redmond, L.C., Morris, P.E., Rupon, J.W., Ginder, G.D., Lloyd, J.A. Blood Cells Mol. Dis. (2005) [Pubmed]
  9. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Carlson, C.M., Endrizzi, B.T., Wu, J., Ding, X., Weinreich, M.A., Walsh, E.R., Wani, M.A., Lingrel, J.B., Hogquist, K.A., Jameson, S.C. Nature (2006) [Pubmed]
  10. Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Sen-Banerjee, S., Mir, S., Lin, Z., Hamik, A., Atkins, G.B., Das, H., Banerjee, P., Kumar, A., Jain, M.K. Circulation (2005) [Pubmed]
  11. Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. Parmar, K.M., Nambudiri, V., Dai, G., Larman, H.B., Gimbrone, M.A., García-Cardeña, G. J. Biol. Chem. (2005) [Pubmed]
  12. Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of MEF2 by NF-kappaB and histone deacetylases. Kumar, A., Lin, Z., SenBanerjee, S., Jain, M.K. Mol. Cell. Biol. (2005) [Pubmed]
  13. Up-regulation of the T cell quiescence factor KLF2 in a leukaemic T-cell line after expression of the inositol 5'-phosphatase SHIP-1. García-Palma, L., Horn, S., Haag, F., Diessenbacher, P., Streichert, T., Mayr, G.W., Jücker, M. Br. J. Haematol. (2005) [Pubmed]
  14. Regulation of the vav proto-oncogene by LKLF. Denkinger, D.J., Cushman-Vokoun, A.M., Kawahara, R.S. Gene (2001) [Pubmed]
  15. WWP1-dependent ubiquitination and degradation of the lung Krüppel-like factor, KLF2. Zhang, X., Srinivasan, S.V., Lingrel, J.B. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  16. Kruppel-like factor 2 inhibits protease activated receptor-1 expression and thrombin-mediated endothelial activation. Lin, Z., Hamik, A., Jain, R., Kumar, A., Jain, M.K. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  17. Angiopoietin-1 induces Kruppel-like factor 2 expression through a phosphoinositide 3-kinase/AKT-dependent activation of myocyte enhancer factor 2. Sako, K., Fukuhara, S., Minami, T., Hamakubo, T., Song, H., Kodama, T., Fukamizu, A., Gutkind, J.S., Koh, G.Y., Mochizuki, N. J. Biol. Chem. (2009) [Pubmed]
  18. Conserved POU-binding site linked to SP1-binding site within FZD5 promoter: Transcriptional mechanisms of FZD5 in undifferentiated human ES cells, fetal liver/spleen, adult colon, pancreatic islet, and diffuse-type gastric cancer. Katoh, Y., Katoh, M. Int. J. Oncol. (2007) [Pubmed]
  19. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Lin, Z., Kumar, A., SenBanerjee, S., Staniszewski, K., Parmar, K., Vaughan, D.E., Gimbrone, M.A., Balasubramanian, V., García-Cardeña, G., Jain, M.K. Circ. Res. (2005) [Pubmed]
  20. Lung Krüppel-like factor contains an autoinhibitory domain that regulates its transcriptional activation by binding WWP1, an E3 ubiquitin ligase. Conkright, M.D., Wani, M.A., Lingrel, J.B. J. Biol. Chem. (2001) [Pubmed]
  21. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Dekker, R.J., van Soest, S., Fontijn, R.D., Salamanca, S., de Groot, P.G., VanBavel, E., Pannekoek, H., Horrevoets, A.J. Blood (2002) [Pubmed]
  22. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Dekker, R.J., Boon, R.A., Rondaij, M.G., Kragt, A., Volger, O.L., Elderkamp, Y.W., Meijers, J.C., Voorberg, J., Pannekoek, H., Horrevoets, A.J. Blood (2006) [Pubmed]
  23. Up-regulation of the KLF2 transcription factor by fluid shear stress requires nucleolin. Huddleson, J.P., Ahmad, N., Lingrel, J.B. J. Biol. Chem. (2006) [Pubmed]
  24. Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Dekker, R.J., van Thienen, J.V., Rohlena, J., de Jager, S.C., Elderkamp, Y.W., Seppen, J., de Vries, C.J., Biessen, E.A., van Berkel, T.J., Pannekoek, H., Horrevoets, A.J. Am. J. Pathol. (2005) [Pubmed]
  25. cDNA isolation, genomic structure, regulation, and chromosomal localization of human lung Kruppel-like factor. Wani, M.A., Conkright, M.D., Jeffries, S., Hughes, M.J., Lingrel, J.B. Genomics (1999) [Pubmed]
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