KLF2
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Krüppel-like Factor 2 (KLF2), also known as lung Krüppel-like Factor (LKLF), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''KLF2''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
on
chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosome ...
. It is in the Krüppel-like factor family of
zinc finger transcription factors Zinc finger transcription factors or ZF-TFs, are transcription factors composed of a zinc finger-binding domain and any of a variety of transcription-factor effector-domains that exert their modulatory effect in the vicinity of any sequence to whic ...
, and it has been implicated in a variety of biochemical processes in the human body, including lung development, embryonic
erythropoiesis Erythropoiesis (from Greek 'erythro' meaning "red" and 'poiesis' "to make") is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is stimulated by decrea ...
,
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
integrity,
T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
viability, and
adipogenesis Adipogenesis is the formation of adipocytes (fat cells) from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as preadipocy ...
.


Discovery

Erythroid Krüppel-like Factor (
EKLF 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 ...
or KLF1) was the first Krüppel-like Factor discovered. It is vital for embryonic erythropoiesis in promoting the switch from fetal
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
(
Hemoglobin F Fetal hemoglobin, or foetal haemoglobin (also hemoglobin F, HbF, or α2γ2) is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream ...
) to adult hemoglobin (Hemoglobin A)
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 ...
by binding to highly conserved CACCC domains. ''EKLF''
ablation Ablation ( la, ablatio – removal) is removal or destruction of something from an object by vaporization, chipping, erosion, erosive processes or by other means. Examples of ablative materials are described below, and include spacecraft materi ...
in mouse embryos produces a lethal
anemic Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
, causing death by embryonic day 14, and natural
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
lead to β+ thalassemia in humans. However, expression of
embryonic hemoglobin The human embryonic haemoglobins were discovered in 1961. These include Hb-Gower 1, consisting of 2 zeta chains and 2 epsilon chains, and Hb-Gower 2, which consists of 2 αlpha-chains and 2 epsilon-chains, the zeta and epsilon chains being the embr ...
and fetal hemoglobin genes is normal in ''EKLF''-deficient mice, and since all genes on the
human β-globin locus The human β-globin locus is composed of five genes located on a short region of chromosome 11, responsible for the creation of the beta parts (roughly half) of the oxygen transport protein Haemoglobin. This locus contains not only the beta globin ...
exhibit the CACCC elements, researchers began searching for other Krüppel-like factors. KLF2, initially called lung Krüppel-like Factor due to its high expression in the adult mouse lung, was first isolated in 1995 by using the
zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
domain of EKLF as a
hybridization probe In molecular biology, a hybridization probe (HP) is a fragment of DNA or RNA of usually 15–10000 nucleotide long which can be radioactively or fluorescently labeled. HP can be used to detect the presence of nucleotide sequences in analyzed RNA ...
. By
transactivation In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein. In the context of recep ...
assay An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a ...
in mouse
fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
, KLF2 was also noticed to bind to the β-globin
gene promoter In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of i ...
containing the CACCC sequence shown to be the binding site for EKLF, confirming KLF2 as a member of the Krüppel-like Factor family. Since then, many other KLF proteins have been discovered.


Structure

The main feature of the KLF family is the presence of three highly conserved
Cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
2/
Histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
2 zinc fingers of either 21 or 23
amino acid residues Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer may ...
in length, located at the
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
of the protein. These amino acid sequences each
chelate Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...
a single zinc ion, coordinated between the two cysteine and two histidine residues. These zinc fingers are joined by a conserved seven-amino acid sequence; T G E K P( Y/ F)X. The zinc fingers enable all KLF proteins to bind to CACCC gene promoters, so although they may complete varied functions (due to lack of
homology Homology may refer to: Sciences Biology *Homology (biology), any characteristic of biological organisms that is derived from a common ancestor * Sequence homology, biological homology between DNA, RNA, or protein sequences *Homologous chrom ...
away from the zinc fingers), they all recognize similar
binding domains In molecular biology, binding domain is a protein domain which binds to a specific atom or molecule, such as calcium or DNA. A protein domain is a part of a protein sequence and a tertiary structure that can change or evolve, function, and live ...
. KLF2 also exhibits these structural features. The
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
transcript is approximately 1.5
kilobase A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s in length, and the 37.7
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
protein contains 354 amino acids. KLF2 also shares some homology with EKLF at the
N-terminus 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 ...
with a
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
-rich region presumed to function as the
transactivation domain The transactivation domain or trans-activating domain (TAD) is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activation ...
.


Gene expression

''KLF2'' was first discovered, and is highly expressed in, the adult mouse
lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
, but it is also expressed temporally during
embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
in erythroid cells,
endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
,
lymphoid cells A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adapt ...
, the
spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .
, and
white adipose tissue White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes. In humans, the healthy amount of white adipose t ...
. It is expressed as early as embryonic day 9.5 in the endothelium. ''KLF2'' has a particularly interesting expression profile in erythroid cells. It is minimally expressed in the primitive and fetal definitive erythroid cells, but is highly expressed in adult definitive erythroid cells, particularly in the
proerythroblast A proerythroblast (or rubriblast, or pronormoblast) is the earliest of four stages in development of the normoblast. In histology, it is very difficult to distinguish it from the other "-blast" cells (lymphoblast, myeloblast, monoblast, and me ...
and the
polychromatic Polychrome is the "practice of decorating architectural elements, sculpture, etc., in a variety of colors." The term is used to refer to certain styles of architecture, pottery or sculpture in multiple colors. Ancient Egypt Colossal statue ...
and orthochromatic normoblasts.


Mouse knockout

Homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
of
embryonic stem cells Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they co ...
was used to generate ''KLF2''-deficient mouse embryos. Both
vasculogenesis Vasculogenesis is the process of blood vessel formation, occurring by a '' de novo'' production of endothelial cells. It is sometimes paired with angiogenesis, as the first stage of the formation of the vascular network, closely followed by ang ...
and
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
were normal in the embryos, but they died by embryonic day 14.5 from severe
hemorrhaging Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
. The
vasculature The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
displayed defective morphology, with thin
tunica media The tunica media (New Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the tunica intima on the inside and the tunica externa on the outside. Artery Tunica media is made up of smooth m ...
and aneurysmal dilation that led to rupturing. Aortic vascular smooth muscle cells failed to organize into a normal tunica media, and
pericytes Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood c ...
were low in number. These ''KLF2''-deficient mice thus demonstrated the important role of ''KLF2'' in blood vessel stabilization during embryogenesis. Due to embryonic lethality in ''KLF2''-deficient embryos, it is difficult to examine the role of ''KLF2'' in normal
post-natal The postpartum (or postnatal) period begins after childbirth and is typically considered to end within 6 weeks as the mother's body, including hormone levels and uterus size, returns to a non-pregnant state. The terms puerperium, puerperal perio ...
physiology Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
, such as in
lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
development and function.


Function


Lung development

Lung buds removed from ''KLF2''-deficient mouse embryos and cultured from normal
tracheobronchial tree The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa. Air is breathed in through the nose to ...
s. In order to circumvent embryonic lethality usually observed in ''KLF2''-deficient embryos, ''KLF2''
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
null mouse embryonic stem cells were constructed and used to produce chimeric animals. These ''KLF2''-deficient embryonic stem cells contribute significantly to development of skeletal muscle, spleen, heart, liver, kidney, stomach, brain, uterus, testis, and skin, but not to the development of the lung. These embryos had lungs arrested in the late canalicular stage of lung development, with undilated acinar tubules. In contrast,
wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
embryos are born in the saccular stage of lung development with expanded alveoli. This suggests that KLF2 is an important
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 ...
required in late gestation for lung development.


Embryonic erythropoiesis

KLF2 is now believed to play an important role in embryonic erythropoiesis, specifically in regulating embryonic and
fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...
β-like globin gene expression. In a
murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families ex ...
''KLF2''-deficient embryo, expression of β-like globin genes normally expressed in primitive erythroid cells was significantly decreased, although
adult An adult is a human or other animal that has reached full growth. In human context, the term ''adult'' has meanings associated with social and legal concepts. In contrast to a " minor", a legal adult is a person who has attained the age of major ...
β-globin gene expression was unaffected. The role of KLF2 in human β-like globin gene expression was further elucidated by
transfection Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: "transformation" is typically used to desc ...
of a murine ''KLF2''-deficient embryo with the human β-globin locus. It was found that KLF2 was important for ε-globin (found in embryonic hemoglobin) and γ-globin (found in
fetal hemoglobin Fetal hemoglobin, or foetal haemoglobin (also hemoglobin F, HbF, or α2γ2) is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream ...
) gene expression. However, as before, KLF2 plays no role in adult β-globin gene expression; this is
regulated Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...
by EKLF. However, KLF2 and EKLF have been found to interact in embryonic erythropoiesis. Deletion of both ''KLF2'' and ''EKLF'' in mouse embryos results in fatal anemia earlier than in either single deletion at embryonic day 10.5. This indicates that KLF2 and EKLF interact in
embryonic Embryonic may refer to: *Of or relating to an embryo * ''Embryonic'' (album), a 2009 studio album by the Flaming Lips *''Embryonics ''Embryonics'' is a double-CD compilation of tracks by the Australian progressive metal band, Alchemist. It w ...
and fetal β-like globin gene expression. It has been shown using conditional knockout mice that both KLF2 and EKLF bind directly to β-like globin promoters. There is also evidence to suggest that KLF2 and EKLF
synergistically Synergy is an interaction or cooperation giving rise to a whole that is greater than the simple sum of its parts. The term ''synergy'' comes from the Attic Greek word συνεργία ' from ', , meaning "working together". History In Christia ...
bind to the ''
Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...
'' promoter, a
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 ...
that is associated with gene expression of α-globin and β-globin in embryonic
proerythroblast A proerythroblast (or rubriblast, or pronormoblast) is the earliest of four stages in development of the normoblast. In histology, it is very difficult to distinguish it from the other "-blast" cells (lymphoblast, myeloblast, monoblast, and me ...
s.


Endothelial physiology

''KLF2'' expression is induced by fluid laminar flow
shear stress Shear stress, often denoted by (Greek: tau), is the component of stress coplanar with a material cross section. It arises from the shear force, the component of force vector parallel to the material cross section. ''Normal stress'', on the ot ...
, as is caused by blood flow in normal endothelium. This activates
mechanosensitive channels Mechanosensitive channels, mechanosensitive ion channels or stretch-gated ion channels (not to be confused with mechanoreceptors). They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They a ...
, which in turn activates two pathways; the MEK5/
ERK5 Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the ''MAPK7'' gene. Function MAPK7 is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical ...
pathway, which activates
MEF2 In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical rol ...
, a
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 ...
that upregulates ''KLF2'' gene expression; and
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
inhibition, which increases the stability of ''KLF2'' mRNA. Binding of cytokines such as
TNFα Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
and
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
to their
receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s activates
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 ...
p65, which also induces ''KLF2'' expression. KLF2 then has four key functions in endothelium: * By inhibiting activation of p65 by transcription coactivator p300, ''
VCAM1 Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the ''VCAM1'' gene. VCAM-1 functions as a cell adhesion molecule. Stru ...
'' and '' SELE'' expression is downregulated, genes that encode endothelial
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s, causing decreased
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
and
leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
activation and hence decreasing inflammation * It upregulates '' THBD'' (thrombomodulin) and '' NOS3'' (endothelial
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 ...
synthase) expression, having an anti-
thrombotic 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 ...
effect * Through the upregulation of ''NOS3'', as well as '' NPPC'' (natriuretic precursor peptide C), KLF2 has a
vasodilatory Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
effect * KLF2 also inhibits ''
VEGFR2 Kinase insert domain receptor (KDR, a type IV receptor tyrosine kinase) also known as vascular endothelial growth factor receptor 2 (VEGFR-2) is a VEGF receptor. ''KDR'' is the human gene encoding it. KDR has also been designated as CD309 (cluster ...
'' (VEGF receptor 2) expression, having an anti-
angiogenic Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...
effect Thus KLF2 has an important role in regulating normal endothelium physiology. It is hypothesized that myeloid-specific KLF2 plays a protective role in
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
. Gene expression changes in endothelial cells induced by KLF2 have been demonstrated to be atheroprotective.


T-cell differentiation

KLF2 has an important function in
T-lymphocyte A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
differentiation. T-cells are activated and more prone to
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 ...
without KLF2, suggesting that KLF2 regulates T-cell
quiescence Quiescence (/kwiˈɛsəns/) is a state of quietness or inactivity. It may refer to: * Quiescence search, in game tree searching (adversarial search) in artificial intelligence, a quiescent state is one in which a game is considered stable and unl ...
and survival. ''KLF2''-deficient
thymocytes A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thym ...
also do not express several receptors required for thymus
emigration Emigration is the act of leaving a resident country or place of residence with the intent to settle elsewhere (to permanently leave a country). Conversely, immigration describes the movement of people into one country from another (to permanentl ...
and differentiation into mature T-cells, such as sphingosine-1 phosphate receptor 1.


Adipogenesis

KLF2 is a
negative regulator A regulator gene, regulator, or regulatory gene is a gene involved in controlling the expression of one or more other genes. Regulatory sequences, which encode regulatory genes, are often at the five prime end (5') to the start site of transcrip ...
of
adipocyte Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
differentiation. KLF2 is expressed in
preadipocytes Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. ...
, but not mature adipocytes, and it potently inhibits PPAR-γ (
peroxisome A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
proliferator-activated receptor-γ) expression by inhibiting promoter activity. This prevents differentiation of preadipocytes into adipocytes, and thus prevents adipogenesis.


See also

*
Krüppel-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. This family has been expanded to also include the Sp transcription factor ...
* Erythroid Krüppel-like factor *
Zinc finger transcription factors Zinc finger transcription factors or ZF-TFs, are transcription factors composed of a zinc finger-binding domain and any of a variety of transcription-factor effector-domains that exert their modulatory effect in the vicinity of any sequence to whic ...


References


External links

* * * {{Transcription factors, g2 Transcription factors