Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q9UID6 (Kruppel-like)
 147 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pokemon 1 is a proto-oncogenic transcriptional regulator that contains a POZ domain at the N-terminus and four Kruppel-like zinc fingers at the C-terminus. Pokemon 1 plays an important role in adipogenesis, osteogenesis, oncogenesis, and transcription of NF-kB responsive genes. Recent reports have shown that biological activities of transcription factors are regulated by sumolylation. We investigated whether Pokemon 1 is post-translationally modified by sumoylation and whether the modification affects Pokemon 1's transcriptional properties. We found that Pokemon 1 is sumoylated in vitro and in vivo. Upon careful analysis of the amino acid sequence of Pokemon 1, we found ten potential sumoylation sites located at lysines 61, 354, 371, 379, 383, 396, 486, 487, 536 and 539. We mutated each of these amino acids into arginine and tested whether the mutation could affect the transcriptional properties of Pokemon 1 on the Pokemon 1 responsive genes, such as ADH5/FDH and pG5-FRE-Luc. Wild-type Pokemon 1 potently represses transcription of ADH5/FDH. Most of the mutants, however, were weaker transcription repressors and repressed transcription 1.3-3.3 fold less effective. Although potential sumoylation sites were located close to the DNA binding domain or the nuclear localization sequence, the mutations did not alter nuclear localization or DNA binding activity. In addition, on the pG5-FRE-Luc test promoter construct, ectopic SUMO-1 repressed transcription in the presence of Pokemon 1. The sumoylation target lysine residue at amino acid 61, which is located in the middle of the POZ-domain, is important because K61R mutation resulted in a much weaker molecular interaction with corepressors. Our data suggest that Pokemon 1's activity as a transcription factor may involve sumoylation, and that sumoylation might be important in the regulation of transcription by Pokemon 1.
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PMID:Regulation of pokemon 1 activity by sumoylation. 1759 26

Monocyte differentiation involves the participation of lineage-restricted transcription factors, although the mechanisms by which this process occurs are incompletely defined. Within the hematopoietic system, members of the Kruppel-like family of factors (KLFs) play essential roles in erythrocyte and T lymphocyte development. Here we show that KLF4/GKLF is expressed in a monocyte-restricted and stage-specific pattern during myelopoiesis and functions to promote monocyte differentiation. Overexpression of KLF4 in HL-60 cells confers the characteristics of mature monocytes. Conversely, KLF4 knockdown blocked phorbol ester-induced monocyte differentiation. Forced expression of KLF4 in primary common myeloid progenitors (CMPs) or hematopoietic stem cells (HSCs) induced exclusive monocyte differentiation in clonogenic assays, whereas KLF4 deficiency inhibited monocyte but increased granulocyte differentiation. Mechanistic studies demonstrate that KLF4 is a target gene of PU.1. Consistently, KLF4 can rescue PU.1-/- fetal liver cells along the monocytic lineage and can activate the monocytic-specific CD14 promoter. Thus, KLF4 is a critical regulator in the transcriptional network controlling monocyte differentiation.
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PMID:The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. 1776 69

Kruppel-like factors (KLFs) are important Sp1-like eukaryotic transcriptional proteins. The LDLR, StAR, and CYP11A genes exhibit GC-rich Sp1-like sites, which have the potential to bind KLFs in multiprotein complexes. We now report that KLF4, KLF9, and KLF13 transcripts are expressed in and regulate ovarian cells. KLF4 and 13, but not KLF9, mRNA expression was induced and then repressed over time (P < 0.001). Combined LH and IGF-I stimulation increased KLF4 mRNA at 2 h (P < 0.01), whereas LH decreased KLF13 mRNA at 6 h (P < 0.05), and IGF-I reduced KLF13 at 24 h (P < 0.01) compared with untreated control. KLF9 was not regulated by either hormone. Transient transfection of KLF4, KLF9, and KLF13 suppressed LDLR/luc, StAR/luc, and CYP11A/luc by 80-90% (P < 0.001). Histone-deacetylase (HDAC) inhibitors stimulated LDLR/luc five- to sixfold and StAR/luc and CYP11A/luc activity twofold (P < 0.001) and partially reversed suppression by all three KLFs (P < 0.001). Deletion of the zinc finger domain of KLF13 abrogated repression of LDLR/luc. Lentiviral overexpression of the KLF13 gene suppressed LDLR mRNA (P < 0.001) and CYP11A mRNA (P = 0.003) but increased StAR mRNA (P = 0.007). Collectively, these data suggest that KLFs may recruit inhibitory complexes containing HDAC corepressors, thereby repressing LDLR and CYP11A transcription. Conversely, KLF13 may recruit unknown coactivators or stabilize StAR mRNA, thereby explaining enhancement of in situ StAR gene expression. These data introduce new potent gonadal transregulators of genes encoding proteins that mediate sterol uptake and steroid biosynthesis.
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PMID:Regulation of Kruppel-like factor 4, 9, and 13 genes and the steroidogenic genes LDLR, StAR, and CYP11A in ovarian granulosa cells. 1805 93

This is the first report to describe a role for Lung Kruppel-like Factor (LKLF or KLF2) in inflammatory airways diseases. In the present study, we identify that LKLF is constitutively expressed in the small airways of normal lungs; however, its expression disappears in severe airway diseases, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. LKLF from primary airway epithelial cells inhibits NF-kappaB-driven transcription induced by Pseudomonas aeruginosa 7-fold, but is down-regulated in the presence of TNF-alpha and activated human neutrophils. As a constitutively expressed protein, LKLF inhibits release of a key pro-inflammatory chemokine, IL-8, from airway epithelia. Its expression by lung epithelial cells is enhanced in the presence of TNF blockade. Thus, cytokine-mediated inhibition of LKLF by neutrophils may contribute to ongoing recruitment by promoting IL-8 release from airway epithelia. We conclude that, in neutrophil-dominated airway environments, such as that seen in CF, reduced LKLF activity releases a brake on pro-inflammatory cytokine production and thereby may contribute to the persistent inflammatory responses seen in CF airway disease.
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PMID:Abrogation of anti-inflammatory transcription factor LKLF in neutrophil-dominated airways. 1821 94

Mutations in the VHL gene are associated with highly vascular tumors of kidney, brain, retina, and adrenal gland. The inability of the mutant VHL protein to destabilize HIF-1 plays a crucial role in malignant angiogenesis. VHL is also associated with ECM assembly but the molecular mechanisms of this activity remain unclear. We used expression arrays and cell lines with different VHL status to identify ECM-associated genes controlled by VHL. One of them, adhesion-associated TGFBI, was repressed by VHL and overexpressed in renal, gastrointestinal, brain, and other tumors. Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia. These data provide the molecular basis for the observed VHL effect on TGFBI and stimulate further research into the KLF10 and TGFBI roles in cancer.
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PMID:Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors. 1835 87

Statins upregulate endothelial thrombomodulin (TM) by mechanisms that involve members of the Kruppel-like factor family. Although Kruppel-like factors are unequivocally implicated in this process, experimental evidence points to additional mechanisms. Deletion/mutation analysis of reporter constructs was used to demonstrate that mutation of the SP1/Kruppel-like factor element in the TM promoter only partially abolishes statin-induced TM upregulation, whereas simultaneous mutation of relevant heat shock elements and SP1/Kruppel-like factor element completely prevents statin-induced TM upregulation, thus demonstrating a role for heat shock factors (HSFs). We further identified the pathway by which statins increase binding of HSF1 to heat shock elements in the TM promoter. Specifically, statins caused NO-dependent dissociation of HSF1 from heat shock protein 90, nuclear translocation of HSF1, and binding to heat shock elements in the TM promoter. Statins also decreased nuclear content of the HSF1 chaperone 14-3-3beta. In addition to reducing TM upregulation, inhibition of HSF1 reduced statin-induced upregulation of tissue plasminogen activator, whereas downregulation of thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor was unaffected. Knockdown of 14-3-3beta or inhibition of HSF1 phosphorylation enhanced the effect of statins on TM and tissue plasminogen activator, but did not influence thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor. These data demonstrate that HSF1 is involved in statin-induced regulation of TM. They also suggest that analogous mechanisms may apply to genes that are upregulated by statins, but not to downregulated genes. These results may have broad implications and suggest the use of heat shock protein modulators to selectively regulate pleiotropic statin effects.
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PMID:Involvement of heat shock factor 1 in statin-induced transcriptional upregulation of endothelial thrombomodulin. 1870 84

Self-renewal of embryonic stem cells (ESCs) is maintained by a complex regulatory mechanism involving transcription factors Oct3/4 (Pou5f1), Nanog and Sox2. Here, we report that Klf5, a Zn-finger transcription factor of the Kruppel-like family, is involved in ESC self-renewal. Klf5 is expressed in mouse ESCs, blastocysts and primordial germ cells, and its knockdown by RNA interference alters the molecular phenotype of ESCs, thereby preventing their correct differentiation. The ability of Klf5 to maintain ESCs in the undifferentiated state is supported by the finding that differentiation of ESCs is prevented when Klf5 is constitutively expressed. Maintenance of the undifferentiated state by Klf5 is, at least in part, due to the control of Nanog and Oct3/4 transcription, because Klf5 directly binds to the promoters of these genes and regulates their transcription.
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PMID:Klf5 is involved in self-renewal of mouse embryonic stem cells. 1865 41

During epithelial homeostasis, stem cells divide to produce progenitor cells, which not only proliferate to generate the cell mass but also respond to cellular signaling to transition from a proliferative state to a differentiation state. Such a transition involves functional alterations of transcriptional factors, yet the underlying molecular mechanisms are poorly understood. Recent studies have implicated Kruppel-like factors (KLFs) including KLF5 in the renewal and maintenance of stem/progenitor cells. Here we demonstrate that the pro-proliferative factor KLF5 becomes anti-proliferative upon TGFbeta-mediated acetylation in an in vitro model of epithelial homeostasis. In the HaCaT epidermal cell line treated with or without TGFbeta, we found that KLF5 was not only essential for cell proliferation, it was also indispensable for TGFbeta-induced anti-proliferation in these cells. KLF5 inhibited the expression of p15 (CDKN2B), a cell cycle inhibitor, without TGFbeta, but became a coactivator in TGFbeta-induced p15 expression in the same cells. Mechanistically, TGFbeta recruited acetylase p300 to acetylate KLF5, and acetylation in turn altered the binding of KLF5 to p15 promoter, resulting in the reversal of KLF5 function. These studies not only demonstrate that a basic transcription factor can be both pro-proliferation and anti-proliferation in epithelial homeostasis, they also present a unique mechanism for how transcriptional regulation changes during the transition from proliferation to inhibition of proliferation. Furthermore, they establish KLF5 as an essential cofactor for TGFbeta signaling.
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PMID:Pro-proliferative factor KLF5 becomes anti-proliferative in epithelial homeostasis upon signaling-mediated modification. 1905 24

Extracellular superoxide dismutase (ECSOD) is a major extracellular antioxidant enzyme that protects organs from damage by reactive oxygen species (ROS). We cloned a novel ECSOD from the bay scallop Argopecten irradians (AiECSOD) by 3' and 5' RACE. The full-length cDNA of AiECSOD was 893bp with a 657bp open reading frame encoding 218 amino acids. The deduced amino acid sequence contained a putative signal peptide of 20 amino acids, and sequence comparison showed that AiECSOD had low degree of homology to ECSODs of other organisms. The genomic length of the AiECSOD gene was about 5276bp containing five exons and six introns. The promoter region contained many putative transcription factor binding sites such as c-Myb, Oct-1, Sp1, Kruppel-like, c-ETS, NFkappaB, GATA-1, AP-1, and Ubx binding sites. Furthermore, tissue-specific expressions of AiECSOD and temporal expressions of AiECSOD in haemocytes of bay scallops challenged with bacteria Vibrio anguillarum were quantified using qRT-PCR. High levels of expression were detected in haemocytes, but not in gonad and mantle. The expression of AiECSOD reached the highest level at 12h post-injection with V. anguillarum and then returned to normal between 24h and 48h post-injection. These results indicated that AiECSOD was an inducible protein and that it may play an important role in the immune responses against V. anguillarum.
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PMID:Cloning, characterization, and expression analysis of extracellular copper/zinc superoxide dismutase gene from bay scallop Argopecten irradians. 1908 69

The transcription factors that regulate endothelial cell development have been a focus of active research for several years, and many players in the endothelial transcriptional program have been identified. This review discusses the function of several major regulators of endothelial transcription, including members of the Sox, Ets, Forkhead, GATA, and Kruppel-like families. This review also highlights recent developments aimed at unraveling the combinatorial mechanisms and transcription factor interactions that regulate endothelial cell specification and differentiation during vasculogenesis and angiogenesis.
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PMID:Transcriptional control of endothelial cell development. 1921 21


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