Kruppel-like factors
Encyclopedia
The Krüppel-like family of transcription factors (Klfs), so named for their homology to the Drosophila melanogaster
Krüppel
protein, have been extensively studied for their roles in cell proliferation, differentiation and survival, especially in the context of cancer . All KLF family members are characterised by their three Cys2 His2 zinc finger
s located at the C-terminus (Fig. 1A), separated by a highly conserved H/C link, (Fig. 1B and C; Fig. 2). DNA binding studies demonstrated that the KLFs have similar affinities for different GC-rich sites, or sites with CACCC homology, and can compete with each other for the occupation of such sites. KLFs also share a high degree of homology between the specificity protein (Sp)
family of zinc-finger transcription factor
s and bind similar, if not the same sites, in a large number of genes.
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.
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.
) in cardiac fibroblast
s 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.
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
Krüppel
Krüppel
Krüppel is a gap gene originally described in Drosophila melanogaster, which encodes a zinc finger transcription factor with four tandemly repeated zinc finger domains....
protein, have been extensively studied for their roles in cell proliferation, differentiation and survival, especially in the context of cancer . All KLF family members are characterised by their three Cys2 His2 zinc finger
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
s located at the C-terminus (Fig. 1A), separated by a highly conserved H/C link, (Fig. 1B and C; Fig. 2). DNA binding studies demonstrated that the KLFs have similar affinities for different GC-rich sites, or sites with CACCC homology, and can compete with each other for the occupation of such sites. KLFs also share a high degree of homology between the specificity protein (Sp)
Sp/KLF family
The Sp/KLF family is a family of transcription factors, including the Kruppel-like factors as well as Sp1, Sp2, Sp3, Sp4, Sp8, Sp9; and possibly Sp5 and Sp7. KLF14 is also designated Sp6....
family of zinc-finger transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s and bind similar, if not the same sites, in a large number of genes.
Members
The following human genes encode Kruppel-like factors:- KLF1, KLF2KLF2Krueppel-like factor 2 is a protein that in humans is encoded by the KLF2 gene....
, KLF3KLF3Krueppel-like factor 3 is a protein that in humans is encoded by the KLF3 gene.KLF3 is a member of the Krüppel-like factors family of transcription factors. KLF3 primarily represses transcription through the transcriptional corepressor C-terminal binding protein...
, KLF4KLF4Krueppel-like factor 4 is a protein that in humans is encoded by the KLF4 gene.. In embryonic stem cells , KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells ....
, KLF5KLF5Krueppel-like factor 5 is a protein that in humans is encoded by the KLF5 gene.-Interactions:KLF5 has been shown to interact with Protein SET....
, KLF6KLF6Krueppel-like factor 6 is a protein that in humans is encoded by the KLF6 gene.It is a tumor suppressor gene.-Interactions:KLF6 has been shown to interact with Sp1 transcription factor.-External links:...
, KLF7KLF7Kruppel-like factor 7 , also known as KLF7, is a protein which in humans is encoded by the KLF7 gene.This protein is a member of the Kruppel-like family of transcription factors....
, KLF8KLF8Krueppel-like factor 8 is a protein that in humans is encoded by the KLF8 gene....
, KLF9KLF9Krueppel-like factor 9 is a protein that in humans is encoded by the KLF9 gene.-Interactions:KLF9 has been shown to interact with Progesterone receptor.... - KLF10KLF10Krueppel-like factor 10 is a protein that in humans is encoded by the KLF10 gene....
, KLF11KLF11Krueppel-like factor 11 is a protein that in humans is encoded by the KLF11 gene....
, KLF12KLF12Krueppel-like factor 12 is a protein that in humans is encoded by the KLF12 gene....
, KLF13KLF13Kruppel-like factor 13, also known as KLF13, is a protein that in humans is encoded by the KLF13 gene.- Function :KLF13 belongs to a family of transcription factors that contain 3 classical zinc finger DNA-binding domains consisting of a zinc atom tetrahedrally coordinated by 2 cysteines and 2...
, KLF14KLF14Krüppel-like factor 14, also known as basic transcription element-binding protein 5 is a protein that in humans is encoded by the KLF14 gene. The corresponding Klf14 mouse gene is known as Sp6.- Function :...
, KLF15KLF15Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.- Expression :...
, KLF16, KLF17KLF17Krueppel-like factor 17 is a protein that in humans is encoded by the KLF17 gene....
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 transactivatesTransactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
the iNOS promoter in cooperation with p65 (RelA
RELA
Transcription factor p65 is a protein that in humans is encoded by the RELA gene.-Interactions:RELA has been shown to interact with NFKBIB, ETHE1, NFKBIE, RFC1, TRIB3, CREB binding protein, Neutrophil cytosolic factor 1, Glucocorticoid receptor, MTPN, BRCA1, C-Fos, POU2F1, BTRC, TATA-binding...
), and the p21Cip1
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
/Waf1 promoter in cooperation with p53, but it directly suppresses the p53 promoter and inhibits ornithine decarboxylase
Ornithine decarboxylase
The enzyme ornithine decarboxylase catalyzes the decarboxylation of ornithine to form putrescine. This reaction is the committed step in polyamine synthesis. In humans, this protein has 461 amino acids and forms a homodimer....
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
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...
and cyclin B1
Cyclin B1
G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene.- Function :Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with to form the maturation-promoting factor...
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
Vascular smooth muscle
Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that is responsible for the...
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
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
, restenosis
Restenosis
Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...
and atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. Klf4 also mediates the vascular response to nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(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
PRKG1
cGMP-dependent protein kinase 1, alpha isozyme is an enzyme that in humans is encoded by the PRKG1 gene.-Interactions:PRKG1 has been shown to interact with ITPR1, RGS2, TNNT1, MRVI1 and GTF2I.-Further reading:...
) 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
RHOA
Ras homolog gene family, member A is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. In humans, it is encoded by the gene 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 (PDGFAPDGFA
Platelet-derived growth factor subunit A is a protein that in humans is encoded by the PDGFA gene.-Further reading:...
) in cardiac fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s a factor previously identified as being upregulated by ET-1, and Klf5+/- transgenic mice heterozygotes (described earlier) exhibited less cardiac fibrosis
Cardiac fibrosis
Cardiac fibrosis refers to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts.Fibrocyte cells normally secrete collagen, and function to provide structural support for the heart...
and hypertrophy
Hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
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.