KLF3 explained

Krüppel-like factor 3 is a protein that in humans is encoded by the KLF3 gene.

Structure

KLF3, originally termed Basic Krüppel-like Factor (BKLF), was the third member of the Krüppel-like factor family of zinc finger transcription factors to be discovered.^[1] Transcription factors in this family bind DNA by virtue of 3 characteristic three C₂H₂ zinc fingers at their C-termini. Since their DNA-binding domains are highly conserved within the family, all KLF proteins recognize CACCC or CGCCC boxes of the general form NCR CRC CCN, (where N is any base and R is a purine).

Function

While the C-termini are similar in different KLFs, the N-termini vary and accordingly different KLFs can either activate or repress transcription or both. KLF3 appears to function predominantly as a repressor of transcription. It turns genes off. It does this by recruiting the C-terminal Binding Protein co-repressors CTBP1 and CTBP2. CtBP docks onto a short motif (residues 61-65) in the N-terminus of KLF3, of the general form Proline – Isoleucine – Aspartate – Leucine – Serine (the PIDLS motif).^[2] CtBP in turn recruits histone modifying enzymes to alter chromatin and repress gene expression.

KLF3 is expressed highly in the red blood cell or erythroid lineage. Here it is driven by another KLF, Erythroid KLF or KLF1, and its expression increases as erythroid cells mature. Studies in knockout mice reveal a mild anemia in the absence of functional KLF3 and the de-repression of several target genes that contain CACCC boxes in their regulatory regions.^[3] Many of these genes are activated by KLF1, hence it appears that KLF3 operates in a negative feedback loop to balance the activating potential of KLF1. KLF3 also regulates another repressive KLF, KLF8.^[4] Thus KLF1, KLF3 and KLF8 operate in a tight regulatory network. KLF3 and KLF8 may have redundant functions, as mice lacking both KLF3 and KLF8 show defects that are more severe than in either single knockout. They die in utero around day 14 of gestation.^[5]

As well as being expressed in erythroid cells, KLF3 is present in other cell types and analysis of the knockout mice has revealed defects affecting adipose tissue^[6] and B cells.^[7] KLF3 deficient mice have less adipose tissue and indications of metabolic health that may be attributable to de-repression of the adipokine hormone gene adipolin.^[8] The role of KLF3 in B lymphocytes is complex but it appears to operate in a network with KLF2 and KLF4 to influence the switch between spleen marginal zone and follicular B cells.^[9]

Interactions

KLF3 has been shown to interact with:

• CTBP2^[2] and
• FHL3.^[10]

Further reading

• Turner J, Crossley M . Basic Krüppel-like factor functions within a network of interacting haematopoietic transcription factors . Int. J. Biochem. Cell Biol. . 31 . 10 . 1169–74 . 2000 . 10582345 . 10.1016/S1357-2725(99)00067-9 .
• Wang MJ, Qu XH, Wang LS, Zhai Y, Wu SL, He FC . cDNA cloning, subcellular localization and tissue expression of a new human Krüppel-like transcription factor: human basic Krüppel-like factor (hBKLF) . Yi Chuan Xue Bao . 30 . 1 . 1–9 . 2003 . 12812068 .
• Perdomo J, Verger A, Turner J, Crossley M . Role for SUMO modification in facilitating transcriptional repression by BKLF . Mol. Cell. Biol. . 25 . 4 . 1549–59 . 2005 . 15684403 . 548027 . 10.1128/MCB.25.4.1549-1559.2005 .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Crossley M . Isolation and Characterization of the cDNA Encoding BKLF/TEF-2, a Major CACCC-Box-Binding Protein in Erythroid Cells and Selected Other Cells . Mol. Cell. Biol. . 16 . 4 . 1695–705 . April 1996 . 231156 . 8657145 . 10.1128/mcb.16.4.1695.
2. Turner J, Crossley M . 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 . 1998 . 9724649 . 1170841 . 10.1093/emboj/17.17.5129 .
3. Funnell AP, Norton LJ, Mak KS, Burdach J, Artuz CM, Twine NA, Wilkins MR, Power CA, Hung TT, Perdomo J, Koh P, Bell-Anderson KS, Orkin SH, Fraser ST, Perkins AC, Pearson RC, Crossley M . The CACCC-binding protein KLF3/BKLF represses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo . Mol. Cell. Biol. . 32 . 16 . 3281–92 . August 2012 . 22711990 . 3434552 . 10.1128/MCB.00173-12 .
4. Eaton SA, Funnell AP, Sue N, Nicholas H, Pearson RC, Crossley M . 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 . August 2008 . 18687676 . 2556010 . 10.1074/jbc.M804831200 . free .
5. Funnell AP, Mak KS, Twine NA, Pelka GJ, Norton LJ, Radziewic T, Power M, Wilkins MR, Bell-Anderson KS, Fraser ST, Perkins AC, Tam PP, Pearson RC, Crossley M . Generation of Mice Deficient in both KLF3/BKLF and KLF8 Reveals a Genetic Interaction and a Role for These Factors in Embryonic Globin Gene Silencing . Mol. Cell. Biol. . 33 . 15 . 2976–87 . August 2013 . 23716600 . 10.1128/MCB.00074-13 . 3719677.
6. Sue N, Jack BH, Eaton SA, Pearson RC, Funnell AP, Turner J, Czolij R, Denyer G, Bao S, Molero-Navajas JC, Perkins A, Fujiwara Y, Orkin SH, Bell-Anderson K, Crossley M . Targeted disruption of the basic Kruppel-like factor gene (Klf3) reveals a role in adipogenesis . Mol Cell Biol . 28 . 12 . 3967–78 . Jun 2008 . 18391014 . 2423134 . 10.1128/MCB.01942-07 .
7. Vu TT, Gatto D, Turner V, Funnell AP, Mak KS, Norton LJ, Kaplan W, Cowley MJ, Agenès F, Kirberg J, Brink R, Pearson RC, Crossley M . Impaired B cell development in the absence of Krüppel-like factor 3 . J. Immunol. . 187 . 10 . 5032–42 . November 2011 . 22003205 . 10.4049/jimmunol.1101450 . free .
8. Bell-Anderson KS, Funnell AP, Williams H, Mat Jusoh H, Scully T, Lim WF, Burdach JG, Mak KS, Knights AJ, Hoy AJ, Nicholas HR, Sainsbury A, Turner N, Pearson RC, Crossley M . Loss of Kruppel-like Factor 3 (KLF3/BKLF) leads to upregulation of the insulin-sensitizing factor adipolin (FAM132A/CTRP12/C1qdc2) . Diabetes . 62 . 8 . 2728–37 . April 2013 . 23633521 . 10.2337/db12-1745 . 3717849.
9. Pearson RC, Funnell AP, Crossley M . The mammalian zinc finger transcription factor Krüppel-like factor 3 (KLF3/BKLF) . IUBMB Life . 63 . 2 . 86–93 . February 2011 . 21360637 . 10.1002/iub.422 . 38842040 . free .
10. Turner J, Nicholas H, Bishop D, Matthews JM, Crossley M . The LIM protein FHL3 binds basic Krüppel-like factor/Krüppel-like factor 3 and its co-repressor C-terminal-binding protein 2 . J. Biol. Chem. . 278 . 15 . 12786–95 . 2003 . 12556451 . 10.1074/jbc.M300587200 . free .