The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Mukesh K. Jain - One of the best experts on this subject based on the ideXlab platform.
-
Kruppel Like Factor 15 regulator of bcaa metabolism and circadian protein rhythmicity
Pharmacological Research, 2017Co-Authors: Paishiun N Hsieh, Liyan Fan, David R Sweet, Mukesh K. JainAbstract:Abstract Regulation of nutrient intake, utilization, and storage exhibits a circadian rhythmicity that allows organisms to anticipate and adequately respond to changes in the environment across day/night cycles. The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important modulators of metabolism and metabolic health – for example, their catabolism yields carbon substrates for gluconeogenesis during periods of fasting. Kruppel-Like Factor 15 (KLF15) has recently emerged as a critical transcriptional regulator of BCAA metabolism, and the absence of this transcription Factor contributes to severe pathologies such as Duchenne muscular dystrophy and heart failure. This review highlights KLF15’s role as a central regulator of BCAA metabolism during periods of fasting, throughout day/night cycles, and in experimental models of muscle disease.
-
experimental lung injury reduces Kruppel Like Factor 2 to increase endothelial permeability via regulation of rapgef3 rac1 signaling
American Journal of Respiratory and Critical Care Medicine, 2017Co-Authors: Ruting Huang, Mukesh K. Jain, Angelo Y Meliton, Matthew Krause, Joyce A Lloyd, Recep Nigdelioglu, Robert B Hamanaka, Anna A Birukova, John P Kress, Konstantin G BirukovAbstract:Rationale: Acute respiratory distress syndrome (ARDS) is caused by widespread endothelial barrier disruption and uncontrolled cytokine storm. Genome-wide association studies (GWAS) have linked multiple genes to ARDS. Although mechanosensitive transcription Factor Kruppel-Like Factor 2 (KLF2) is a major regulator of endothelial function, its role in regulating pulmonary vascular integrity in lung injury and ARDS-associated GWAS genes remains poorly understood.Objectives: To examine KLF2 expression in multiple animal models of acute lung injury and further elucidate the KLF2-mediated pathways involved in endothelial barrier disruption and cytokine storm in experimental lung injury.Methods: Animal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis Factor-α, LPS, mechanical stretch/ventilation, or microvascular flow. KLF2 manipulation, permeability measurements, small GTPase activity, l...
-
Kruppel Like Factor 15 mediates glucocorticoid induced restoration of podocyte differentiation markers
Journal of The American Society of Nephrology, 2017Co-Authors: Sandeep K Mallipattu, Agnieszka B. Bialkowska, Yiqing Guo, Monica P Revelo, Lucia Roapena, Timothy Miller, Jason Ling, Stuart J Shankland, Chelsea Estrada, Mukesh K. JainAbstract:Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Kruppel-Like Factor 15 (KLF15), a kidney-enriched zinc finger transcription Factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte.
-
Kruppel Like Factor 2 suppresses mammary carcinoma growth by regulating retinoic acid signaling
Oncotarget, 2015Co-Authors: Wei Zhang, Mukesh K. Jain, Pallab Banerjee, Liraz Levi, Noa NoyAbstract:The transcription Factor Kruppel-Like Factor 2 (KLF2) displays anticarcinogenic activities but the mechanism that underlies this activity is unknown. We show here that KLF2 is markedly downregulated in human breast cancers and that its expression positively correlates with breast cancer patient survival. We show further that KLF2 suppresses tumor development by controlling the transcriptional activity of the vitamin A metabolite retinoic acid (RA). RA regulates gene transcription by activating two types of nuclear receptors: RA receptors (RARs), which inhibit tumor development, and peroxisome proliferator-activated receptor β/δ (PPARβ/δ), which promotes tumorigenesis. The partitioning of RA between these receptors is regulated by two carrier proteins: cellular retinoic acid-binding protein 2 (CRABP2), which delivers RA to RARs, and fatty acid-binding protein 5 (FABP5), which shuttles ligands to PPARβ/δ. We show that KLF2 induces the expression of CRABP2 and RARγ and inhibits the expression FABP5 and PPARβ/δ thereby shifting RA signaling from the pro-carcinogenic FABP5/PPARβ/δ to the growth-suppressing CRABP2/RAR path. The data thus reveal that KLF2 suppresses tumor growth by controlling the transcriptional activities of RA.
-
reduced Kruppel Like Factor 2 expression may aggravate the endothelial injury of diabetic nephropathy
Kidney International, 2015Co-Authors: Mukesh K. Jain, Fang Zhong, Habing Chen, Chengguo Wei, Weijia Zhang, Peter Y Chuang, Hongyu Chen, Yongjun WangAbstract:Kruppel-Like Factor 2 (KLF2), a shear stress–inducible transcription Factor, has endoprotective effects. In streptozotocin-induced diabetic rats, we found that glomerular Klf2 expression was reduced in comparison with nondiabetic rats. However, normalization of hyperglycemia by insulin treatment increased Klf2 expression to a level higher than that of nondiabetic rats. Consistent with this, we found that Klf2 expression was suppressed by high glucose but increased by insulin in cultured endothelial cells. To determine the role of KLF2 in streptozotocin-induced diabetic nephropathy, we used endothelial cell–specific Klf2 heterozygous knockout mice and found that diabetic knockout mice developed more kidney/glomerular hypertrophy and proteinuria than diabetic wild-type mice. Glomerular expression of Vegfa , Flk1 , and angiopoietin 2 increased, but expression of Flt1 , Tie2 , and angiopoietin 1 decreased, in diabetic knockout mice compared with diabetic wild-type mice. Glomerular expression of ZO-1, glycocalyx, and eNOS was also decreased in diabetic knockout compared with diabetic wild-type mice. These data suggest knockdown of Klf2 expression in the endothelial cells induced more endothelial cell injury. Interestingly, podocyte injury was also more prominent in diabetic knockout compared with diabetic wild-type mice, indicating a cross talk between these two cell types. Thus, KLF2 may play a role in glomerular endothelial cell injury in early diabetic nephropathy.
Vincent W. Yang - One of the best experts on this subject based on the ideXlab platform.
-
Kruppel Like Factor 4 klf4 what we currently know
Gene, 2017Co-Authors: Amr M. Ghaleb, Vincent W. YangAbstract:Kruppel-Like Factor 4 (KLF4) is an evolutionarily conserved zinc finger-containing transcription Factor that regulates diverse cellular processes such as cell growth, proliferation, and differentiation. Since its discovery in 1996, KLF4 has been gaining a lot of attention, particularly after it was shown in 2006 as one of four Factors involved in the induction of pluripotent stem cells (iPSCs). Here we review the current knowledge about the different functions and roles of KLF4 in various tissue and organ systems.
-
Kruppel Like Factor 4 modulates development of bmi1 intestinal stem cell derived lineage following γ radiation induced gut injury in mice
Stem cell reports, 2016Co-Authors: Jes G Kuruvilla, Amr M. Ghaleb, Agnieszka B. Bialkowska, Vincent W. YangAbstract:In response to ionizing radiation-induced injury, the normally quiescent intestinal stem cells marked by BMI1 participate in the regenerative response. Previously, we established a protective role for Kruppel-Like Factor 4 (KLF4) in the intestinal epithelium where it reduces senescence, apoptosis, and crypt atrophy following γ-radiation-induced gut injury. We also described a pro-proliferative function for KLF4 during the regenerative phase post irradiation. In the current study, using a mouse model in which Klf4 is deleted from quiescent BMI1+ intestinal stem cells, we observed increased proliferation from the BMI1+ lineage during homeostasis. In contrast, following irradiation, Bmi1-specific Klf4 deletion leads to decreased expansion of the BMI1+ lineage due to a combination of reduced proliferation and increased apoptosis. Our results support a critical role for KLF4 in modulating BMI1+ intestinal stem cell fate in both homeostasis and the regenerative response to radiation injury.
-
Kruppel Like Factor 4 is a radioprotective Factor for the intestine following γ radiation induced gut injury in mice
American Journal of Physiology-gastrointestinal and Liver Physiology, 2015Co-Authors: Daniel Talmasov, Agnieszka B. Bialkowska, Vincent W. Yang, Jes G Kuruvilla, Mandayam O Nandan, Zhang Xinjun, Enas Elkarim, Amr M. GhalebAbstract:Gut radiation-induced injury is a concern during treatment of patients with cancer. Kruppel-Like Factor 4 (KLF4) is expressed in differentiated villous epithelial cells of the small intestine. We p...
-
altered intestinal epithelial homeostasis in mice with intestine specific deletion of the Kruppel Like Factor 4 gene
Developmental Biology, 2011Co-Authors: Amr M. Ghaleb, Klaus H Kaestner, Beth B Mcconnell, Vincent W. YangAbstract:The zinc finger transcription Factor, Kruppel-Like Factor 4 (KLF4), is expressed in the post-mitotic, differentiated epithelial cells lining the intestinal tract and exhibits a tumor suppressive effect on intestinal tumorigenesis. Here we report a role for KLF4 in maintaining homeostasis of intestinal epithelial cells. Mice with conditional ablation of the Klf4 gene from the intestinal epithelium were viable. However, both the rates of proliferation and migration of epithelial cells were increased in the small intestine of mutant mice. In addition, the brush-border alkaline phosphatase was reduced as was expression of ephrine-B1 in the small intestine, resulting in mispositioning of Paneth cells to the upper crypt region. In the colon of mutant mice, there was a reduction of the differentiation marker, carbonic anhydrase-1, and failure of differentiation of goblet cells. Mechanistically, deletion of Klf4 from the intestine resulted in activation of genes in the Wnt pathway and reduction in expression of genes encoding regulators of differentiation. Taken together, these data provide new insights into the function of KLF4 in regulating postnatal proliferation, migration, differentiation, and positioning of intestinal epithelial cells and demonstrate an essential role for KLF4 in maintaining normal intestinal epithelial homeostasis in vivo.
-
notch inhibits expression of the Kruppel Like Factor 4 tumor suppressor in the intestinal epithelium
Molecular Cancer Research, 2008Co-Authors: Amr M. Ghaleb, Agnieszka B. Bialkowska, Gaurav Aggarwal, Mandayam O Nandan, Vincent W. YangAbstract:The zinc finger-containing transcription Factor, Kruppel-Like Factor 4 (KLF4), inhibits cell proliferation. An in vivo tumor-suppressive role for KLF4 is shown by the recent finding that Klf4 haploinsufficiency in ApcMin/+ mice promotes intestinal tumorigenesis. Studies also show that KLF4 is required for the terminal differentiation of goblet cells in the mouse intestine. The Notch signaling pathway suppresses goblet cell formation and is up-regulated in intestinal tumors. Here, we investigated the relationship between Notch signaling and KLF4 expression in intestinal epithelial cells. The rate of proliferation of HT29 human colon cancer cells was reduced when treated with the γ-secretase inhibitor dibenzazepine to inhibit Notch signaling or small interfering RNA directed against Notch. KLF4 levels were increased in dibenzazepine-treated or Notch small interfering RNA-treated cells. Conversely, overexpression of Notch in HT29 cells reduced KLF4 levels, suppressed KLF4 promoter activity, and increased proliferation rate. Treatment of ApcMin/+ mice with dibenzazepine resulted in a 50% reduction in the number of intestinal adenomas compared with the vehicle-treated group (P
Susan Gray - One of the best experts on this subject based on the ideXlab platform.
-
the Kruppel Like Factor klf15 inhibits connective tissue growth Factor ctgf expression in cardiac fibroblasts
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Baiqiu Wang, Osama A Ibrahim, Sudeshna Fisch, Andrew Leask, Susan Gray, Yuan Lu, Saptarsi M. Haldar, Mukesh K. JainAbstract:Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth Factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription Factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-β1 (TGFβ1) strongly reduces KLF15 expression while inducing the pro-fibrotic Factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFβ1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15 −/− mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFβ1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the coactivator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
-
the Kruppel Like Factor klf15 inhibits connective tissue growth Factor ctgf expression in cardiac fibroblasts
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Baiqiu Wang, Osama A Ibrahim, Sudeshna Fisch, Andrew Leask, Susan Gray, Saptarsi M. Haldar, Mukesh K. JainAbstract:Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth Factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription Factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-beta1 (TGFbeta1) strongly reduces KLF15 expression while inducing the pro-fibrotic Factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
-
the Kruppel Like Factor klf2 inhibits peroxisome proliferator activated receptor gamma expression and adipogenesis
Journal of Biological Chemistry, 2003Co-Authors: Sucharita Sen Banerjee, Susan Gray, Mark W Feinberg, Masafumi Watanabe, Richard L Haspel, Diane J Denkinger, Rodney S Kawahara, Hans Hauner, Mukesh K. JainAbstract:Abstract Obesity is an important public health problem associated with a number of disease states such as diabetes and arteriosclerosis. As such, an understanding of the mechanisms governing adipose tissue differentiation and function is of considerable importance. We recently reported that the Kruppel-Like zinc finger transcription Factor KLF15 can induce adipocyte maturation and GLUT4 expression. In this study, we identify that a second family member, KLF2/Lung Kruppel-Like Factor (LKLF), as a negative regulator of adipocyte differentiation. KLF2 is highly expressed in adipose tissue, and studies in cell lines and primary cells demonstrate that KLF2 is expressed in preadipocytes but not mature adipocytes. Constitutive overexpression of KLF2 but not KLF15 potently inhibits peroxisome proliferator-activated receptor-γ (PPARγ) expression with no effect on the upstream regulators C/EBPβ and C/EBPδ. However, the expression of C/EBPα and SREBP1c/ADD1 (adipocyte determination and differentiation Factor-1/sterol regulatory element-binding protein-1), two Factors that feedback in a positive manner to enhance PPARγ function, was also markedly reduced. In addition, transient transfection studies show that KLF2 directly inhibits PPARγ2 promoter activity (70% inhibition;p < 0.001). Using a combination of promoter mutational analysis and gel mobility shift assays, we have identified a binding site within the PPARγ2 promoter, which mediates this inhibitory effect. These data identify a novel role for KLF2 as a negative regulator of adipogenesis.
-
the Kruppel Like Factor klf2 inhibits peroxisome proliferator activated receptor γ expression and adipogenesis
Journal of Biological Chemistry, 2003Co-Authors: Sucharita Sen Banerjee, Susan Gray, Mark W Feinberg, Masafumi Watanabe, Richard L Haspel, Diane J Denkinger, Rodney S Kawahara, Hans Hauner, Mukesh K. JainAbstract:Obesity is an important public health problem associated with a number of disease states such as diabetes and arteriosclerosis. As such, an understanding of the mechanisms governing adipose tissue differentiation and function is of considerable importance. We recently reported that the Kruppel-Like zinc finger transcription Factor KLF15 can induce adipocyte maturation and GLUT4 expression. In this study, we identify that a second family member, KLF2/Lung Kruppel-Like Factor (LKLF), as a negative regulator of adipocyte differentiation. KLF2 is highly expressed in adipose tissue, and studies in cell lines and primary cells demonstrate that KLF2 is expressed in preadipocytes but not mature adipocytes. Constitutive overexpression of KLF2 but not KLF15 potently inhibits peroxisome proliferator-activated receptor-γ (PPARγ) expression with no effect on the upstream regulators C/EBPβ and C/EBPδ. However, the expression of C/EBPα and SREBP1c/ADD1 (adipocyte determination and differentiation Factor-1/sterol regulatory element-binding protein-1), two Factors that feedback in a positive manner to enhance PPARγ function, was also markedly reduced. In addition, transient transfection studies show that KLF2 directly inhibits PPARγ2 promoter activity (70% inhibition;p
Mark W Feinberg - One of the best experts on this subject based on the ideXlab platform.
-
Kruppel Like Factor 4 regulates endothelial inflammation
Journal of Biological Chemistry, 2007Co-Authors: Anne Hamik, Ajay Kumar, Zhiyong Lin, Mark W Feinberg, Mercedes Balcells, Sumita Sinha, Jonathan P Katz, Robert E Gerzsten, Elazer R Edelman, Mukesh K. JainAbstract:The vascular endothelium plays a critical role in vascular homeostasis. Inflammatory cytokines and non-laminar blood flow induce endothelial dysfunction and confer a pro-adhesive and pro-thrombotic phenotype. Therefore, identification of Factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Kruppel-Like Factor 4 expression has been documented in endothelial cells, but a function has not been described. In this communication we describe the expression in vitro and in vivo of Kruppel-Like Factor 4 in human and mouse endothelial cells. Furthermore, we demonstrate that endothelial Kruppel-Like Factor 4 is induced by pro-inflammatory stimuli and shear stress. Overexpression of Kruppel-Like Factor 4 induces expression of multiple anti-inflammatory and anti-thrombotic Factors including endothelial nitric-oxide synthase and thrombomodulin, whereas knockdown of KruppelLike Factor 4 leads to enhancement of tumor necrosis Factor α-induced vascular cell adhesion molecule-1 and tissue Factor expression. The functional importance of Kruppel-Like Factor 4 is verified by demonstrating that Kruppel-Like Factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface and prolongs clotting time under inflammatory states. Kruppel-Like Factor 4 differentially regulates the promoter activity of pro- and anti-inflammatory genes in a manner consistent with its anti-inflammatory function. These data implicate Kruppel-Like Factor 4 as a novel regulator of endothelial activation in response to pro-inflammatory stimuli.
-
Kruppel Like Factor 2 klf2 regulates proinflammatory activation of monocytes
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Hiranmoy Das, Ajay Kumar, Zhiyong Lin, Mark W Feinberg, Willmar D Patino, Paul M Hwang, Pradip K Majumder, Mukesh K. JainAbstract:The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-Like Factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory Factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-κB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated Factor. These observations identify KLF2 as a novel negative regulator of monocytic activation.
-
Kruppel Like Factor 4 is a mediator of proinflammatory signaling in macrophages
Journal of Biological Chemistry, 2005Co-Authors: Mark W Feinberg, Sucharita Senbanerjee, Zhuoxiao Cao, Akm Khyrul Wara, Maria A Lebedeva, Mukesh K. JainAbstract:Activation of macrophages is important in chronic inflammatory disease states such as atherosclerosis. Proinflammatory cytokines such as interferon-γ (IFN-γ), lipopolysaccharide (LPS), or tumor necrosis Factor-α can promote macrophage activation. Conversely, anti-inflammatory Factors such as transforming growth Factor-β1 (TGF-β1) can decrease proinflammatory activation. The molecular mediators regulating the balance of these opposing effectors remain incompletely understood. Herein, we identify Kruppel-Like Factor 4 (KLF4) as being markedly induced in response to IFN-γ, LPS, or tumor necrosis Factor-α and decreased by TGF-β1 in macrophages. Overexpression of KLF4 in J774a macrophages induced the macrophage activation marker inducible nitric-oxide synthase and inhibited the TGF-β1 and Smad3 target gene plasminogen activator inhibitor-1 (PAI-1). Conversely, KLF4 knockdown markedly attenuated the ability of IFN-γ, LPS, or IFN-γ plus LPS to induce the iNOS promoter, whereas it augmented macrophage responsiveness to TGF-β1 and Smad3 signaling. The KLF4 induction of the iNOS promoter is mediated by two KLF DNA-binding sites at –95 and –212 bp, and mutation of these sites diminished induction by IFN-γ and LPS. We further provide evidence that KLF4 interacts with the NF-κB family member p65 (RelA) to cooperatively induce the iNOS promoter. In contrast, KLF4 inhibited the TGF-β1/Smad3 induction of the PAI-1 promoter independent of KLF4 DNA binding through a novel antagonistic competition with Smad3 for the C terminus of the coactivator p300/CBP. These findings support an important role for KLF4 as a regulator of key signaling pathways that control macrophage activation.
-
the Kruppel Like Factor klf2 inhibits peroxisome proliferator activated receptor gamma expression and adipogenesis
Journal of Biological Chemistry, 2003Co-Authors: Sucharita Sen Banerjee, Susan Gray, Mark W Feinberg, Masafumi Watanabe, Richard L Haspel, Diane J Denkinger, Rodney S Kawahara, Hans Hauner, Mukesh K. JainAbstract:Abstract Obesity is an important public health problem associated with a number of disease states such as diabetes and arteriosclerosis. As such, an understanding of the mechanisms governing adipose tissue differentiation and function is of considerable importance. We recently reported that the Kruppel-Like zinc finger transcription Factor KLF15 can induce adipocyte maturation and GLUT4 expression. In this study, we identify that a second family member, KLF2/Lung Kruppel-Like Factor (LKLF), as a negative regulator of adipocyte differentiation. KLF2 is highly expressed in adipose tissue, and studies in cell lines and primary cells demonstrate that KLF2 is expressed in preadipocytes but not mature adipocytes. Constitutive overexpression of KLF2 but not KLF15 potently inhibits peroxisome proliferator-activated receptor-γ (PPARγ) expression with no effect on the upstream regulators C/EBPβ and C/EBPδ. However, the expression of C/EBPα and SREBP1c/ADD1 (adipocyte determination and differentiation Factor-1/sterol regulatory element-binding protein-1), two Factors that feedback in a positive manner to enhance PPARγ function, was also markedly reduced. In addition, transient transfection studies show that KLF2 directly inhibits PPARγ2 promoter activity (70% inhibition;p < 0.001). Using a combination of promoter mutational analysis and gel mobility shift assays, we have identified a binding site within the PPARγ2 promoter, which mediates this inhibitory effect. These data identify a novel role for KLF2 as a negative regulator of adipogenesis.
-
the Kruppel Like Factor klf2 inhibits peroxisome proliferator activated receptor γ expression and adipogenesis
Journal of Biological Chemistry, 2003Co-Authors: Sucharita Sen Banerjee, Susan Gray, Mark W Feinberg, Masafumi Watanabe, Richard L Haspel, Diane J Denkinger, Rodney S Kawahara, Hans Hauner, Mukesh K. JainAbstract:Obesity is an important public health problem associated with a number of disease states such as diabetes and arteriosclerosis. As such, an understanding of the mechanisms governing adipose tissue differentiation and function is of considerable importance. We recently reported that the Kruppel-Like zinc finger transcription Factor KLF15 can induce adipocyte maturation and GLUT4 expression. In this study, we identify that a second family member, KLF2/Lung Kruppel-Like Factor (LKLF), as a negative regulator of adipocyte differentiation. KLF2 is highly expressed in adipose tissue, and studies in cell lines and primary cells demonstrate that KLF2 is expressed in preadipocytes but not mature adipocytes. Constitutive overexpression of KLF2 but not KLF15 potently inhibits peroxisome proliferator-activated receptor-γ (PPARγ) expression with no effect on the upstream regulators C/EBPβ and C/EBPδ. However, the expression of C/EBPα and SREBP1c/ADD1 (adipocyte determination and differentiation Factor-1/sterol regulatory element-binding protein-1), two Factors that feedback in a positive manner to enhance PPARγ function, was also markedly reduced. In addition, transient transfection studies show that KLF2 directly inhibits PPARγ2 promoter activity (70% inhibition;p
Jinkun Wen - One of the best experts on this subject based on the ideXlab platform.
-
mir 146a and Kruppel Like Factor 4 form a feedback loop to participate in vascular smooth muscle cell proliferation
EMBO Reports, 2011Co-Authors: Shaoguang Sun, Bin Zheng, Mei Han, Xinmei Fang, Suibing Miao, Yi Han, Huijing Shi, Jinkun WenAbstract:MicroRNAs are phenotypic regulators of vascular smooth muscle cells (VSMCs). In this paper, we demonstrate that miR-146a targets the Kruppel-Like Factor 4 (KLF4) 3′-untranslated region and has an important role in promoting VSMC proliferation in vitro and vascular neointimal hyperplasia in vivo. Silencing of miR-146a in VSMCs increases KLF4 expression, whereas overexpression of miR-146a decreases KLF4 levels. Furthermore, we demonstrate that KLF4 competes with Kruppel-Like Factor 5 (KLF5) to bind to and regulate the miR-146a promoter, and that KLF4 and KLF5 exert opposing effects on the miR-146a promoter. Overexpression of KLF4 in VSMCs decreases miR-146a transcription levels. By using both gain-of-function and loss-of-function approaches, we found that miR-146a promotes VSMC proliferation in vitro. Transfection of antisense miR-146a oligonucleotide into balloon-injured rat carotid arteries markedly decreased neointimal hyperplasia. These findings suggest that miR-146a and KLF4 form a feedback loop to regulate each other's expression and VSMC proliferation.
-
role of Kruppel Like Factor 4 in phenotypic switching and proliferation of vascular smooth muscle cells
Iubmb Life, 2010Co-Authors: Bin Zheng, Mei Han, Jinkun WenAbstract:Phenotypic switching and proliferation of vascular smooth muscle cells (VSMCs) are critical components in the development of many vascular proliferation diseases such as atherosclerosis and restenosis after percutaneous coronary interventions. Kruppel-Like Factor 4 (KLF4) has been shown to play a key role in VSMC proliferation and differentiation. The focus of this review is to provide an overview for understanding the physiological and pathobiological roles of KLF4 in phenotypic switching and proliferation of VSMCs.
