Krüppel-like factors
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In molecular genetics, the Krüppel-like family of
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s (KLFs) are a set of
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
C2H2 zinc finger DNA-binding proteins that regulate
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
. This family has been expanded to also include the Sp transcription factor and related proteins, forming the Sp/KLF family.


Members

The following human genes encode Kruppel-like factors:
KLF1 Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturatio ...
, KLF2, KLF3, KLF4,
KLF5 Krueppel-like factor 5 is a protein that in humans is encoded by the ''KLF5'' gene. Function This gene encodes a member of the Kruppel-like factor subfamily of zinc finger proteins. Since the protein localizes to the nucleus and binds the epid ...
,
KLF6 Krueppel-like factor 6 is a protein that in humans is encoded by the ''KLF6'' gene. It is a tumor suppressor gene. Function This gene encodes a nuclear protein that has three zinc fingers at the end of its C-terminal domain, a serine/threonin ...
,
KLF7 Kruppel-like factor 7 (ubiquitous), 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 factor In molecular biology, a transcription factor ( ...
, KLF8, KLF9, KLF10,
KLF11 Krueppel-like factor 11 is a protein that in humans is encoded by the ''KLF11'' gene. KLF11 is a mesoderm derived, zinc finger transcription factor in the Krüppel-like factor (KLF) family. It binds to SP1- like GC- rich sequences in epsilon and ...
,
KLF12 Krueppel-like factor 12 is a protein that in humans is encoded by the ''KLF12'' gene. Activator protein-2 alpha (AP-2 alpha) is a developmentally-regulated transcription factor and important regulator of gene expression during vertebrate developm ...
, KLF13, KLF14,
KLF15 Krüppel-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 Activated glucocorticoid recepto ...
, KLF16,
KLF17 Krueppel-like factor 17 is a protein that in humans is encoded by the ''KLF17'' gene. Model organisms Model organisms have been used in the study of KLF17 function. A conditional knockout mouse line called ''Klf17tm1b(KOMP)Wtsi'' was generated ...
The following genes are Sp factors: Sp1, Sp2, Sp3, Sp4, Sp5, Sp6, Sp7, Sp8, and Sp9. Note that although KLF14 was an alias for Sp6 (), it now refers to a protein () derived from KLF16 by a retrotransposon event.


Function and properties

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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, as well as the development and homeostasis of several types of tissue. The C-terminal end binds to the promoter and enhancer regions of a gene. Each KLF also has a unique amino-terminal (
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
) 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. These transcription factors have a conserved structural homology between mammalian species, which allow for similar function due to similar protein interaction motifs at the N-terminal domains. The C-terminal end is also highly conserved with both the first and second zinc finger have 25 amino acids, while the third has 23 amino acids. Each of the three zinc fingers recognize three unique base pairs for their DNA-binding sites, which together make the general form NCR CRC CCN (where N is any base and R is a purine). There is some evidence that positively-charged amino acids within the three zinc fingers may contribute towards localizing the protein in the Nucleus. The N-terminal end allows for the binding of various coactivators, corepressors, and modifiers. All family members share the zinc finger signature KLF-DBD of CxxxxCxxxxxxxxxxxxHxxxHxxxxxxxCxxxxCxxxxxxxxxxxxHxxxHxxxxxxxCxxCxxxxxxxxxxxxHxxxH and use a 9aaTAD. KLFs are divided into three subgroups; Group 1 (KLF 3,8, and 12) are
repressors In molecular genetics, a repressor is a DNA-binding protein, DNA- or RNA-binding protein that inhibits the Gene expression, expression of one or more genes by binding to the Operator (biology), operator or associated Silencer (DNA), silencers. ...
via interaction with the C-terminal Binding Protein 1 and 2 (
CtBP1 C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the ''CTBP1'' gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2. Function The CtBP1 protein was originally identified as a human prote ...
and CtBP2). Group 2 (KLFs 1,2,4,5,6, and 7) are
transcription activators A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and, ...
. Group 3 (KLFs 9,10,11,13,12, and 16) have repressor activity via interaction with the common transcriptional co-repressor,
Sin3A Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the ''SIN3A'' gene. Function The protein encoded by this gene is a transcriptional regulatory protein. It contains paired amphipathic helix (PAH) domains, which a ...
. KLFs 15 and 17 are distantly related without any defined protein interaction motifs. The Sp family members diverged from KLFs since
Filozoa The Filozoa are a monophyletic grouping within the Opisthokonta. They include animals and their nearest unicellular relatives (those organisms which are more closely related to animals than to fungi or Mesomycetozoa). Three groups are currentl ...
. They are typically divided into two groups of Sp1-4 and Sp5-9. One of the signatures is the "Btd box" CxCPxC preceding the KLF-DBD.


Evolutionary and biochemical mechanisms

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 Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturatio ...
, originally known as Erythroid KLF (EKLF) is expressed only in red blood cells and megakaryocytes. It drives red blood cell differentiation and represses megakaryocyte formation. It appears that it has arisen as a KLF family member that has a particular role in these two blood lineages. Other KLFs are more broadly expressed and there are interactions between family members. KLF3 for instance is driven by
KLF1 Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturatio ...
as is KLF8. 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 Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturatio ...
is a very important factor in red cell biology. Naturally occurring human mutations in the
KLF1 Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturatio ...
gene have been associated with de-repression of the fetal globin gene. KLF2 (originally Lung KLF ) also has a role in embryonic globin gene expression, 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 th
four genes
that can reprogram body cells to become stem cells. LF4is one of the so-called magic four transcription factors, KLF4, Oct4, Sox2 and Myc.
KLF5 Krueppel-like factor 5 is a protein that in humans is encoded by the ''KLF5'' gene. Function This gene encodes a member of the Kruppel-like factor subfamily of zinc finger proteins. Since the protein localizes to the nucleus and binds the epid ...
, like KLF3, is important in adipocytes and KLF6 is an important tumour suppressor gene, that is often mutated in prostate cancers.


Krüppel-like factor 3

KLF3 has a short motif in the N-terminus (of the form Proline-Isoleucine-Aspartate-Leucine-Serine or PIDLS) that recruits CtBP1 and 2. 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.


Krüppel-like factors 4 and 5

Klf4, also known 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 Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and perista ...
promoter in cooperation with p65 (
RelA Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the ''RELA'' gene. RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear tran ...
), and the
p21Cip1 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
/Waf1 promoter in cooperation with p53, but it directly suppresses the p53 promoter and inhibits ornithine decarboxylase ( ODC) promoter activity by competing with specificity protein-1 ( Sp-1). Klf4 also interacts with the
p300/CBP The p300-CBP coactivator family in humans is composed of two closely related transcriptional co-activating proteins (or coactivators): #p300 (also called EP300 or E1A binding protein p300) # CBP (also known as CREB-binding protein or CREBBP) ...
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 but, similar to Klf4, binds p300 which acetylates the first zinc finger conferring a trans-activating function. Importantly for Klf4 and Klf5, the amino acids that are predicted to interact with DNA are identical and the two compete for the same CACCC element or GC-rich sequence of the gene promoter region to regulate cell proliferation or differentiation-elated gene expression. 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. 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 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
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. The Wnt/ APC signal 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 causes of klf4 gene silencing.


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 Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
, restenosis and atherosclerosis. Klf4 also mediates the vascular response to
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(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 Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...
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. KLF-2 activation has been associated with laminar blood flow, a key protective force in the arterial walls that helps prevent atherosclerosis since it induces a protective phenotype in endothelial cells. In low-shear stress regions, KLF-2 inhibits a mechanosensory complex composed of platelet endothelial cell adhesion molecule (PECAM-1), vascular endothelial cadherin (VE-cadherin), and vascular endothelial growth factor receptor 2/3 (VEGFR2/3).


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 Platelet-derived growth factor subunit A is a protein that in humans is encoded by the ''PDGFA'' gene. The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors ...
) in cardiac
fibroblast A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
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 Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...
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 Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
.


In genomic engineering

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.


References


External links

*
Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4

PTHR23235
PANTHER family encompassing KLF/Sp {{Transcription factors, g2 Molecular genetics Transcription factors