KLF15
Encyclopedia
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.
upregulates the expression of KLF15.
KLF15 is increased by fasting and decreased by feeding and insulin via PI3K
signalling. KLF15 was increased by glucocorticoid signalling and was also increased by inhibition of PI3K. Insulin and its counteracting hormones regulate the hepatic expression of KLF15. Forced expression of KLF15 in cultured hepatocytes increased both the expression and the promoter activity of the gene for phosphoenolpyruvate carboxykinase
(PEPCK).
KLF15 in adipose tissue is down-regulated in obese mice. aP2-KLF15 Tg mice which overexpress KLF15 manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. The enhancement of insulin secretion resulted from down-regulation of stearoyl-CoA desaturase-1
(SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in WAT of aP2-KLF15 Tg mice exhibited increased oxidative stress in WAT, reduced insulin secretion with hyperglycemia. The data indicates an example of cross talk between white adipose tissue and pancreatic β cells
mediated through modulation of oxidative stress.
Using deletion and mutation analysis, EMSA and ChIP, demonstrated that USF1 and Spl can bind to E-box in-80 to-45 and GC-box in-189 to-155 in the KLF15 promoter respectively, thus regulating the transcription of KLF15 gene.
promoter leading to the upregulation of testosterone
production. In addition KLF15 overexpression in combination with insulin, glucocorticoid, and cAMP stimulated adipogenesis in H295R cells. In silico and RT-PCR analyses showed that the KLF15 gene promoter undergoes alternative splicing in a tissue-specific manner
KLF15 is a strong and direct activator of BMPER
expression which is inhibited by SP1
. BMPER
is inhibited by endothelin-1, which may be mediated by endothelin inhibition of KLF15.
The LRP5
promoter has a KLF15 binding site.
KLF15 specifically interacts with MEF2A and synergistically activates the GLUT4
promoter via an intact KLF15-binding site proximal to the MEF2A site. Cardiac and skeletal muscle expressed miR-133
regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.
Transforming growth factor-beta1 (TGFbeta1
) strongly reduces KLF15 expression. Adenoviral
overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF
expression in neonatal rat ventricular fibroblasts. Hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. KLF15 is implicated as a novel negative regulator of CTGF expression and cardiac fibrosis.
KLF15 inhibits myocardin. TGFbeta mediated activation of p38 MAPK
decreases KLF15 permitting the upreg of myocardin and stimulate the expression of serum response factor target genes, such as atrial natriuretic factor eventually leading to left ventricular hypertrophy which often progresses to heart failure.
The combination of KLF15 and Sp1
resulted in a synergistic activation of the acetyl-CoA synthetase 2 (AceCS2) promoter. AceCS2 produces acetyl-CoA for oxidation through the citric acid cycle
in the mitochondrial matrix. Fasting upregulated KLF15 which upregulated AceCS2.
Progesterone receptor
-mediated induction of Krüppel-like factor 15 (KLF15), which can bind to GC-rich DNA within the E2F1
promoter, is required for maximal induction of E2F1
expression by progestin
s.
KLF15 may function as an inhibitor of cardiac hypertrophycan by the inhibition of GATA4
and MEF2
.
REDD1 and KLF15 are direct target genes of the glucocorticoid receptor (GR) in skeletal muscle. KLF15 inhibits mTOR activity via a distinct mechanism involving BCAT2 gene activation. KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1
and SMuRF1
genes and negatively modulates myofiber size.
KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid-degrading enzymes and that the inhibitory effect of metformin
on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes.
Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.
The expression of the KLF15 gene is markedly up-regulated during the differentiation of 3T3-L1 preadipocytes into adipocytes. Ectopic expression of KLF15 in NIH 3T3 or C2C12 cells triggered both lipid accumulation and the expression of PPARgamma in the presence of inducers of adipocyte differentiation. Ectopic expression of C/EBPbeta, C/EBPdelta, or C/EBPalpha in NIH 3T3 cells also elicited the expression of KLF15 in the presence of inducers of adipocyte differentiation. KLF15 and C/EBPalpha act synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes demonstrating that KLF15 plays an essential role in adipogenesis in 3T3-L1 cells through its regulation of PPAR gamma expression.}
The minimal transactivation domain of erythroid Krüppel-like factor EKLFTAD) has two functional subdomains EKLFTAD1 and EKLFTAD2 of which EKLFTAD2 is conserved in KLF15. EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300.
KLF15 is a novel transcriptional activator for HBV core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the KLF15 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in the Krüppel-like factor
Kruppel-like factors
The Krüppel-like family of transcription factors , 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...
family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.
Expression
Activated glucocorticoid receptorGlucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
upregulates the expression of KLF15.
KLF15 is increased by fasting and decreased by feeding and insulin via PI3K
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
signalling. KLF15 was increased by glucocorticoid signalling and was also increased by inhibition of PI3K. Insulin and its counteracting hormones regulate the hepatic expression of KLF15. Forced expression of KLF15 in cultured hepatocytes increased both the expression and the promoter activity of the gene for phosphoenolpyruvate carboxykinase
Phosphoenolpyruvate carboxykinase
Phosphoenolpyruvate carboxykinase is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.It is found in two forms, cytosolic and mitochondrial....
(PEPCK).
KLF15 in adipose tissue is down-regulated in obese mice. aP2-KLF15 Tg mice which overexpress KLF15 manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. The enhancement of insulin secretion resulted from down-regulation of stearoyl-CoA desaturase-1
Stearoyl-CoA desaturase-1
Stearoyl-CoA desaturase is a protein that in humans is encoded by the SCD gene.Stearoyl-CoA desaturase-1is a key enzyme in fatty acid metabolism. It is responsible for forming a double bond in Stearoyl-CoA...
(SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in WAT of aP2-KLF15 Tg mice exhibited increased oxidative stress in WAT, reduced insulin secretion with hyperglycemia. The data indicates an example of cross talk between white adipose tissue and pancreatic β cells
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
mediated through modulation of oxidative stress.
Using deletion and mutation analysis, EMSA and ChIP, demonstrated that USF1 and Spl can bind to E-box in-80 to-45 and GC-box in-189 to-155 in the KLF15 promoter respectively, thus regulating the transcription of KLF15 gene.
Gene regulation
KLF15 binding site in the HSD17B5AKR1C3
Aldo-keto reductase family 1 member C3 is an enzyme that in humans is encoded by the AKR1C3 gene.-Further reading:...
promoter leading to the upregulation of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
production. In addition KLF15 overexpression in combination with insulin, glucocorticoid, and cAMP stimulated adipogenesis in H295R cells. In silico and RT-PCR analyses showed that the KLF15 gene promoter undergoes alternative splicing in a tissue-specific manner
KLF15 is a strong and direct activator of BMPER
BMPER
BMP binding endothelial regulator is a protein that in humans is encoded by the BMPER gene.-Transcription:KLF15 is a strong and direct activator of BMPER expression which is inhibited by SP1. BMPER is inhibited by endothelin-1, which may be mediated by endothelin inhibition of KLF15....
expression which is inhibited by SP1
SP1
SP1 may refer to :* Bowlus SP-1 Paper Wing, glider* SP-1 switch, a late 60's telecommunications switch by Northern Electric* Sp1 transcription factor, a human protein* Dallara SP1, a race car...
. BMPER
BMPER
BMP binding endothelial regulator is a protein that in humans is encoded by the BMPER gene.-Transcription:KLF15 is a strong and direct activator of BMPER expression which is inhibited by SP1. BMPER is inhibited by endothelin-1, which may be mediated by endothelin inhibition of KLF15....
is inhibited by endothelin-1, which may be mediated by endothelin inhibition of KLF15.
The LRP5
LRP5
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene.- Function :LRP5 is a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis...
promoter has a KLF15 binding site.
KLF15 specifically interacts with MEF2A and synergistically activates the GLUT4
GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
promoter via an intact KLF15-binding site proximal to the MEF2A site. Cardiac and skeletal muscle expressed miR-133
Mir-133 microRNA precursor family
mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice and homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with...
regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.
Transforming growth factor-beta1 (TGFbeta1
TGF beta 1
Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis...
) strongly reduces KLF15 expression. Adenoviral
Adenoviridae
Adenoviruses are medium-sized , nonenveloped icosahedral viruses composed of a nucleocapsid and a double-stranded linear DNA genome...
overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF
CTGF
CTGF is a cysteine-rich, matrix-associated, heparin-binding protein. In vitro, CTGF mirrors some of the effects of TGF beta on skin fibroblasts, such as stimulation of extracellular matrix production, chemotaxis, proliferation and integrin expression...
expression in neonatal rat ventricular fibroblasts. Hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. KLF15 is implicated as a novel negative regulator of CTGF expression and cardiac fibrosis.
KLF15 inhibits myocardin. TGFbeta mediated activation of p38 MAPK
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....
decreases KLF15 permitting the upreg of myocardin and stimulate the expression of serum response factor target genes, such as atrial natriuretic factor eventually leading to left ventricular hypertrophy which often progresses to heart failure.
The combination of KLF15 and Sp1
Sp1
Sp1, also known as Specificity Protein 1, is a human transcription factor involved in gene expression in the early development of an organism. It belongs to the Sp/KLF family of transcription factors. The protein is 785 amino acids long, with a molecular weight of 81 kDA...
resulted in a synergistic activation of the acetyl-CoA synthetase 2 (AceCS2) promoter. AceCS2 produces acetyl-CoA for oxidation through the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
in the mitochondrial matrix. Fasting upregulated KLF15 which upregulated AceCS2.
Progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
-mediated induction of Krüppel-like factor 15 (KLF15), which can bind to GC-rich DNA within the E2F1
E2F1
Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene.-Interactions:E2F1 has been shown to interact with NCOA6, Retinoblastoma-like protein 1, Retinoblastoma protein, GTF2H1, SKP2, PURA, NPDC1, Sp2 transcription factor, Sp1 transcription factor, CUL1, ARID3A, TOPBP1,...
promoter, is required for maximal induction of E2F1
E2F1
Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene.-Interactions:E2F1 has been shown to interact with NCOA6, Retinoblastoma-like protein 1, Retinoblastoma protein, GTF2H1, SKP2, PURA, NPDC1, Sp2 transcription factor, Sp1 transcription factor, CUL1, ARID3A, TOPBP1,...
expression by progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
s.
KLF15 may function as an inhibitor of cardiac hypertrophycan by the inhibition of GATA4
GATA4
Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.-Interactions:GATA4 has been shown to interact with NKX2-5, TBX5, ZFPM2, Serum response factor and HAND2.HDAC2- External links :...
and MEF2
Mef2
In the field of molecular biology, myocyte enhancer factor-2 proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical role in embryonic development. In adult organisms, Mef2...
.
REDD1 and KLF15 are direct target genes of the glucocorticoid receptor (GR) in skeletal muscle. KLF15 inhibits mTOR activity via a distinct mechanism involving BCAT2 gene activation. KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1
FBXO32
F-box only protein 32 is a protein that in humans is encoded by the FBXO32 gene.-Further reading:...
and SMuRF1
SMURF1
E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the SMURF1 gene.-Interactions:SMURF1 has been shown to interact with ARHGEF9, PLEKHO1 and SMURF2.-Further reading:...
genes and negatively modulates myofiber size.
KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid-degrading enzymes and that the inhibitory effect of metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes.
Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.
The expression of the KLF15 gene is markedly up-regulated during the differentiation of 3T3-L1 preadipocytes into adipocytes. Ectopic expression of KLF15 in NIH 3T3 or C2C12 cells triggered both lipid accumulation and the expression of PPARgamma in the presence of inducers of adipocyte differentiation. Ectopic expression of C/EBPbeta, C/EBPdelta, or C/EBPalpha in NIH 3T3 cells also elicited the expression of KLF15 in the presence of inducers of adipocyte differentiation. KLF15 and C/EBPalpha act synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes demonstrating that KLF15 plays an essential role in adipogenesis in 3T3-L1 cells through its regulation of PPAR gamma expression.}
The minimal transactivation domain of erythroid Krüppel-like factor EKLFTAD) has two functional subdomains EKLFTAD1 and EKLFTAD2 of which EKLFTAD2 is conserved in KLF15. EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300.
KLF15 is a novel transcriptional activator for HBV core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication