Kruppel-like factors
In
Members
The following human genes encode Kruppel-like factors: KLF1, KLF2, KLF3, KLF4, KLF5, KLF6, KLF7, KLF8, KLF9, KLF10, KLF11, KLF12, KLF13, KLF14, KLF15, KLF16, KLF17
The following genes are Sp factors:
.Note that although KLF14 was an alias for Sp6 (Q3SY56), it now refers to a protein (Q8TD94) derived from KLF16 by a retrotransposon event.[3]
Function and properties
This section is missing information about Sp phylogeny.(August 2019) |
KLF/Sps are a family of transcription factors that contain three carboxyl-terminal (
CxxxxCxxxxxxxxxxxxHxxxHxxxxxxxCxxxxCxxxxxxxxxxxxHxxxHxxxxxxxCxxCxxxxxxxxxxxxHxxxH
and use a 9aaTAD.[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). Group 2 (KLFs 1,2,4,5,6, and 7) are transcription activators. Group 3 (KLFs 9,10,11,13,12, and 16) have repressor activity via interaction with the common transcriptional co-repressor, Sin3A. KLFs 15 and 17 are distantly related without any defined protein interaction motifs.[4]
The Sp family members diverged from KLFs since Filozoa. 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.[3]
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, 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.[6] Other KLFs are more broadly expressed and there are interactions between family members. KLF3 for instance is driven by KLF1 as is KLF8.[7] 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 is a very important factor in red blood cell biology. Naturally occurring human mutations in the KLF1 gene have been associated with de-repression of the fetal globin gene.[8] KLF2 (originally Lung KLF[9] ) also has a role in embryonic globin gene expression,[10] 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 the four genes that can reprogram body cells to become stem cells. [KLF4] is one of the so-called magic four transcription factors, KLF4, Oct4, Sox2 and Myc. KLF5, like KLF3, is important in adipocytes[11] and KLF6 is an important tumour suppressor gene, that is often mutated in prostate cancers.[12]
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.[13] 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
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
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).[14]
In the myocardium
Little is known of the Klfs in the myocardium. Klf5 activates the promoter of the hypertrophic agonist platelet derived growth factor (
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
- Kruppel-like+transcription+factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4
- PTHR23235: PANTHER family encompassing KLF/Sp