Kruppel-like factors

The Krüppel-like family of transcription factors (KLFs) are a set of zinc finger DNA-binding proteins that regulate gene expression.

Members

The following human genes encode Kruppel-like factors: KLF1, KLF2, KLF3, KLF4, KLF5, KLF6, KLF7, KLF8, KLF9, KLF10, KLF11, KLF12, KLF13, KLF14, KLF15, KLF16, KLF17

Summary

Each family member has a characteristic set of three zinc fingers at its C-terminus. These fingers are related to those of the archetypal Drosophila melanogaster regulatory protein Krüppel. Hence the family is named after Kruppel and family members numbered roughly in the order in which they were discovered.[1]

In mammals there are 17 genes in the KLF family. In addition, there are also 9 related proteins that form the SP1 subfamily. The transcription factors SP1 to SP9 are similar to the KLFs but their zinc fingers are more in the middle of the protein rather than at the C-terminus.[2]

The Significance of KLFs

The family is important since it nicely illustrates general features found in transcription factor families and gene families generally.

Firstly, these transcription factors have a simple and well understood structure. Their characteristic zinc finger DNA-binding domain at the C-terminus contains 3 zinc fingers, that each essentially recognize 3 base pairs in DNA. Thus the DNA-binding site recognized by these proteins is of the general form NCR CRC CCN (where N is any base and R is a purine). The functional domains of the KLFs are at the other end of the protein, the N-terminus, and vary between family members. Thus some KLFs activate and others repress gene expression. Some do both. In several cases the mechanisms by which the functional N-terminal domains operate is understood. In the case of KLF3, for example, there is a short motif in the N-terminus (of the form Proline-Isoleucine-Aspartate-Leucine-Serine or PIDLS) that recruits the co-repressor proteins C-terminal Binding Protein 1 and 2 (CTBP1 and CTBP2).[3] CtBP in turn recruits histone modifying enzymes. It brings in histone deacetylases, histone demethylases and histone methylases, which are thought to remove active chromatin marks and lay down repressive marks to eliminate gene expression.

The understanding of the structure and function of KLFs has informed the design of artificial transcription factors. Artificial zinc fingers can be built to recognize chosen sites in DNA and artificial functional domains can be added to either activate or repress genes containing these sites.

The proliferation of KLF genes, presumably from an ancestral KLF, is also interesting. In some cases different family members are expressed in different tissues. The first KLF, KLF1, originally known as Erythroid KLF (EKLF) is expressed only in red blood cells and megakaryocytes. It drives red blood cell differentiation and represses megaryocyte formation. It appears that it has arisen as a KLF family member that has a particular role in these two blood lineages.[4] Other KLFs are more broadly expressed and there are interactions between family members. KLF3 for instance is driven by KLF1 as is KLF8.[5] On the other hand, KLF3 represses KLF8. Such cross-regulation occurs extensively in transcription factor families. Many transcription factor genes regulate their own promoters and when a gene duplicates during evolution then cross-regulation often occurs. The cross-regulation can ensure that the total amount of KLFs in the cell is monitored and controlled.

Finally, the biological roles of the KLFs are of wide interest. KLF1 is a very important factor in red cell biology. Naturally occurring human mutations in the KLF1 gene have been associated with de-repression of the fetal globin gene.[6] KLF2 (originally Lung KLF[7] ) also has a role in embryonic globin gene expression,[8] as does KLF3 (originally Basic KLF). KLF3 also has roles in adipocyte or fat formation, and in B lymphocytes. Recently, KLF3 was shown to be important in heart development. KLF4 (originally Gut KLF) is an important gene in the gut and skin but has more recently risen to prominence as one of the four genes that can reprogram body cells to become stem cells. [KLF4] is one of the so-called magic four transcription factors, KLF4, Oct4, Sox2 and Myc. KLF5, like KLF3, is important in adipocytes[9] and KLF6 is an important tumour suppressor gene, that is often mutated in prostate cancers.[10]

For a comprehensive review of KLFs see.[11]

Details on Krüppel-like factors 4 & 5

Klf4 (Fig. 2A), known also as gut-enriched Krüppel-like factor (GKLF) acts as a transcriptional activator or repressor depending on the promoter context and/or cooperation with other transcription factors. For example, Klf4 transactivates the iNOS promoter in cooperation with p65 (RelA), and the p21Cip1/Waf1 promoter in cooperation with p53, but it directly suppresses the p53 promoter and inhibits ornithine decarboxylase promoter activity by competing with specificity protein-1 (Sp-1). Klf4 also interacts with the p300/CBP transcription co-activators. Klf5, also known as intestinal enriched Krüppel-like factor (IKLF) or basic transcription element binding protein 2 (Bteb2) has been assigned purely transcriptional activation activity (Fig. 1A) but, similar to Klf4, binds p300 which acetylates the first zinc finger conferring a trans-activating function. Importantly for Klf4 & Klf5, the amino acids that are predicted by the Klevit model to interact with DNA are identical (Fig. 1B and Fig. 2) and the two compete for the same CACCC element found in a wide variety of promoters. Klf4 & Klf5 can act antagonistically during cellular proliferation, differentiation, and promoter activation, either via direct competition or via alterations in their own gene expression. The expression of Klf4 in terminally differentiated, post-mitotic intestinal epithelial cells as opposed to proliferating crypt cells which contain high levels of Klf5 is one example of such opposing effects . Klf4 inhibits proliferation through activation of p21Cip1/Waf1, and direct suppression of cyclin D1 and cyclin B1 gene expression. Both Klf4 & Klf5 proteins act on the Klf4 promoter where Klf4 increases expression and Klf5 decreases expression of Klf4 mRNA.

Krüppel-like factors 4 & 5 in the vascular system

Klf4 is upregulated in vascular injury. It dramatically represses SRF/myocardin-induced activation of gene expression, and directly inhibits myocardin gene expression in vascular smooth muscle cells (VSMCs), therefore inhibiting the transition to a proliferative phenotype . Furthermore, Klf4 has been identified as an anti-proliferative shear stress-responsive gene, and forced over-expression of Klf4 in VSMCs induces growth arrest. Klf4 may therefore be an important protective factor in disease states affected by shear stress, such as thrombosis, restenosis and atherosclerosis. Klf4 also mediates the vascular response to nitric oxide (NO) by activating the promoters of inducible nitric oxide synthase (iNOS) in endothelial cells and cGMP-dependent protein kinase 1α/protein kinase G 1α (PKG 1α) in VSMCs. PKG 1α is activated by NO and mediates VSMC relaxation. This trans-activating effect of Klf4 on the PKG 1α promoter is inhibited by RhoA-induced actin polymerisation, possibly via G-actin regulation of a Klf4 co-activator or co-repressor. RhoA signalling pathways and RhoA activation are implicated in hypertension and increased vascular resistance which to some extent can be explained by this interaction with Klf4 and its effects on the response to NO. Klf5 has no effect on the PKG 1α promoter though the protein expression and nuclear localisation of Klf5 was similar to that of Klf4.

Krüppel-like factors 4 & 5 in the myocardium

Little is known of the Klfs in the myocardium. Klf5 activates the promoter of the hypertrophic agonist platelet derived growth factor (PDGFA) in cardiac fibroblasts a factor previously identified as being upregulated by ET-1, and Klf5+/- transgenic mice heterozygotes (described earlier) exhibited less cardiac fibrosis and hypertrophy when stimulated with angiotensin II compared with controls. Klf5 is itself regulated by the immediate early gene egr-1 in VSMCs, which, if similarly regulated in the cardiomyocyte, places Klf5 potentially in a position to co-ordinate the acute response to external stress and tissue remodelling in the myocardium.

References

  1. ↑ Turner, Jeremy; Merlin Crossley (June 1999). "Mammalian Krüppel-like transcription factors: more than just a pretty finger.". Trends in Biochemical Sciences 24 (6): 236–40. doi:10.1016/s0968-0004(99)01406-1. PMID 10366853.
  2. ↑ Suske, G.; Bruford, E.; Philipsen, S. (May 2005). "Mammalian SP/KLF transcription factors: bring in the family.". Genomics 85 (5): 551–6. doi:10.1016/j.ygeno.2005.01.005. PMID 15820306.
  3. ↑ Turner J, Crossley M (1998). "Cloning and characterization of mCtBP2, a co-repressor that associates with basic Krüppel-like factor and other mammalian transcriptional regulators". EMBO J. 17 (17): 5129–40. doi:10.1093/emboj/17.17.5129. PMC 1170841. PMID 9724649.
  4. ↑ Miller, I.; Bieker, J. (May 1993). "A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins.". Mol. Cell. Biol. 13 (5): 2776–86. PMC 359658. PMID 7682653.
  5. ↑ Eaton, Sally; Funnell AP; Sue N; Nicholas H; Pearson RC; Crossley M. (August 2008). "A network of Krüppel-like Factors (Klfs). Klf8 is repressed by Klf3 and activated by Klf1 in vivo.". J. Biol. Chem. 283 (40): 26937–47. doi:10.1074/jbc.M804831200. PMC 2556010. PMID 18687676.
  6. ↑ Borg, Joseph; George P. Patrinos; Alex E. Felice; Sjaak Philipsen (May 2011). "Erythroid phenotypes associated with KLF1 mutations". Haematologica 96 (5): 635–638. doi:10.3324/haematol.2011.043265. PMC 3084906. PMID 21531944.
  7. ↑ Anderson, KP; Kern CB; Crable SC; Lingrel JB. (Nov 1995). "Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Krüppel-like factor: identification of a new multigene family.". Mol. Cell. Biol. 15 (11): 5957–65. PMC 230847. PMID 7565748.
  8. ↑ Basu P, Morris PE, Haar JL, Wani MA, Lingrel JB, Gaensler KML & Lloyd JA (2005). "Klf2 is essential for primitive erythropoiesis and regulates the human and murine embryonic β-like globin genes in vivo". Blood 106 (7): 2566–2571. doi:10.1182/blood-2005-02-0674. PMC 1895257. PMID 15947087.
  9. ↑ Oishi, Y; Manabe I, Tobe K, Tsushima K, Shindo T, Fujiu K, Nishimura G, Maemura K, Yamauchi T, Kubota N, Suzuki R, Kitamura T, Akira S, Kadowaki T, Nagai R. (Jan 2005). "Krüppel-like transcription factor KLF5 is a key regulator of adipocyte differentiation.". Cell Metabolism 1 (1): 27–39. doi:10.1016/j.cmet.2004.11.005. PMID 16054042. Cite uses deprecated parameter |coauthors= (help)
  10. ↑ Narla, G; Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA, Friedman SL. (Dec 2001). "KLF6, a candidate tumor suppressor gene mutated in prostate cancer.". Science 294 (5551): 2563–6. doi:10.1126/science.1066326. PMID 11752579. Cite uses deprecated parameter |coauthors= (help)
  11. ↑ McConnell, B; Yang, V. (Oct 2010). "Mammalian Krüppel-like factors in health and diseases.". Physiol. Rev. 90 (4): 1337–81. doi:10.1152/physrev.00058.2009. PMC 2975554. PMID 20959618.

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