Kruppel-like factors
In molecular genetics, the Krüppel-like family of transcription factors (KLFs) are a set of eukaryotic C2H2 zinc finger DNA-binding proteins that regulate gene expression.
[3] KLF/Sps are a family of transcription factors that contain three carboxyl-terminal (C-terminal) C2H2-type zinc finger structural motifs that bind to the GC-rich regions in DNA and regulate various cellular functions, such as proliferation, differentiation, and apoptosis, as well as the development and homeostasis of several types of tissue.
Each KLF also has a unique amino-terminal (N-terminal) end that acts as the functional domain that allows it to bind specifically to a certain partner.
KLFs share the similar function of transcription regulation via the recruitment of regulatory proteins.
There is some evidence that positively-charged amino acids within the three zinc fingers may contribute towards localizing the protein in the Nucleus.
[3] KLFs are divided into three subgroups; Group 1 (KLF 3,8, and 12) are repressors via interaction with the C-terminal Binding Protein 1 and 2 (CtBP1 and CtBP2).
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 but, similar to Klf4, binds p300 which acetylates the first zinc finger conferring a trans-activating function.
Klf4 and Klf5 can act antagonistically during cellular proliferation, differentiation, and promoter activation, either via direct competition or via alterations in their own gene expression.
LOH, point mutations in the coding region and promoter hypermethylation are the main causes of klf4 gene silencing.
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.
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.
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.
The understanding of the structure and function of KLFs has informed the design of artificial transcription factors.
