In molecular genetics, the Kruppel-like transcription factor family (KLFs) is a group of eukaryotic C2H2 zinc finger DNA-binding proteins that regulate gene expression. The family has expanded to include Sp transcription factors and related proteins to form the Sp/KLF family.
Function and properties
KLF/Sps is a series of transcription factors containing three carboxy-terminal (C-terminal) C2H2-type zinc finger structure motifs that bind to GC-rich regions of DNA and regulate various cellular functions such as proliferation, differentiation and cell death. Death, as well as the development and homeostasis of several types of tissues. The C-terminus binds to the promoter and enhancer regions of the gene. Each KLF also has a unique amino terminus (N-terminus) that acts as a functional domain allowing it to specifically bind to a certain partner. KLF has a similar transcriptional regulatory function by recruiting regulatory proteins. These transcription factors have conserved structural homology between mammalian species, which allows for similar functions due to similar protein interaction motifs at the N-terminal domain. The C-terminus is also highly conserved, with the first and second zinc fingers having 25 amino acids and the third zinc terminal having 23 amino acids. Each of the three zinc fingers recognizes three unique base pairs of their DNA binding sites, which together form the general form of NCR CRC CCN (where N is any base and R is a purine). There is evidence that positively charged amino acids within the three zinc fingers may help locate proteins in the nucleus. The N-terminus allows for the combination of various coactivators, co-repressors and modifiers.
KLF is divided into three groups; Group 1 (KLF3, KLF8 and KLF12) is a repressor that interacts with C-terminal binding proteins 1 and 2 (CtBP1 and CtBP2). Group 2 (KLF1, KLF2, KLF4, KLF5, KLF6 and KLF7) is a transcriptional activator. Group 3 (KLF9, KLF10, KLF11, KLF13, KLF12 and KLF16) has repressor activity by interaction with the co-transcriptional co-repressor Sin3A. KLF15 and 17 are distantly related and do not have any defined protein interaction motifs. Since Filoloa, members of the Sp family have been separated from KLF: they are usually divided into two groups, Sp1-4 and Sp5-9. One of the signatures is the "Btd box" CxCPxC before the KLF-DBD.
Kruppel-like factor 3
KLF3 has a short motif at the N-terminus (proline-isoleucine-aspartate-leucine-serine or PIDLS form), which recruits CtBP1 and CtBP2. CtBP in turn to recruit histone modifying enzymes. It brings together histone deacetylases, histone demethylases and histone methylases, which are thought to remove active chromatin markers and produce inhibitory markers to eliminate gene expression.
Figure 1. Structure of Kruppel-like factor 3
Kruppel-like factors 4 and 5
KLF4, also known as the enteric-rich Kruppel-like factor (GKLF), acts as a transcriptional activator or repressor depending on the promoter background and/or cooperation with other transcription factors. KLF4 also interacts with the p300/CBP transcriptional coactivator (Figure 2). KLF5, also known as intestinal enrichment of Kruppel-like factor (IKLF) or basic transcriptional element binding protein 2 (Bteb2), has been designated as a pure transcriptional activation activity, but similar to KLF4, in combination with p300, acetylated the first zinc finger Give trans-activation. Importantly, for KLF4 and KLF5, the amino acids predicted to interact with DNA are identical, and both compete for the same GCCCC element or GC-rich sequence of the gene promoter region to regulate gene expression associated with cell proliferation or differentiation. KLF4 and KLF5 can antagonize cell proliferation, differentiation and promoter activation through direct competition or through changes in their own gene expression. In contrast to proliferating crypt cells containing high levels of Klf5, expression of KLF4 in terminally differentiated mitotic intestinal epithelial cells is an example of this opposite effect. KLF4 inhibits proliferation by activating p21Cip1/Waf1 and directly inhibits the expression of cyclin D1 and cyclin B1 genes. Both KLF4 and KLF5 proteins act on the KLF4 promoter, with KLF4 increasing expression and Klf5 decreasing KLF4 mRNA expression. The Wnt/APC signaling pathway also plays an important role in the regulation of KLF4 expression. LOH, point mutations in the coding region and promoter hypermethylation are the main reasons for KLF4 gene silencing.
Figure 2. Crystallographic structure of p300/CBP transcription co-activatorsm.
1. Fernandez-Zapico ME.; et al. A functional family-wide screening of SP/KLF proteins identifies a subset of suppressors of KRAS-mediated cell growth. The Biochemical Journal. 2011,435 (2): 529–37.
2. Borg J.; et al. Erythroid phenotypes associated with KLF1 mutations. Haematologica. 2011,96 (5): 635–8.