Disease relevance of KLF1

• We also propose that absence of AHSP in EKLF-null red cells exacerbates the toxicity of free alpha-globin chains, which exist because of the defect in beta-globin gene activation [1].
• The DNA-binding domains (DBDs) of several zinc finger proteins, including EKLF, interact directly with SWI/SNF to generate DNase I hypersensitivity within the chromatin-assembled beta-globin promoter [2].
• Availability of human EKLF will enable initiation of studies to molecularly assess whether it is functionally compromised in those cases of beta-thalassemia that contain a normal beta-globin gene locus [3].
• Furthermore, the shear stress response region of the KLF2 promoter was specifically immunoprecipitated by antibodies against acetylated histones H3 and H4 in shear-stressed but not static hemangioendothelioma cells [4].
• Northern blot analysis was used to study RNA expression in human colon cancer RKO cells engineered to overexpress KLF4 [5].

High impact information on KLF1

• Erythroid Krüppel-like factor (EKLF) is necessary for stage-specific expression of the human beta-globin gene [6].
• A SWI/SNF-related chromatin remodeling complex, E-RC1, is required for tissue-specific transcriptional regulation by EKLF in vitro [6].
• EKLF contains three zinc-fingers homologous to those found in the Krüppel family of transcription factors [7].
• Heterozygous EKLF+/- mice show that the reporter gene is expressed in a developmentally specific manner in all types of erythroblasts in the fetal liver and adult bone marrow [7].
• We conclude that the transcription factor EKLF is essential for the final steps of definitive erythropoiesis in fetal liver [7].

Biological context of KLF1

• The Krüppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-gamma expression and adipogenesis [8].
• The proximal element is absolutely conserved, but does not bind EKLF as it is not a canonical binding site [1].
• The Krüppel-like factor (KLF) family is a recently highlighted group of zinc finger transcription factors given their important biological roles which include the vasculature [9].
• Interestingly, we find that two SWI/SNF subunits (BRG1 and BAF155) are necessary and sufficient for targeted chromatin remodeling and transcriptional activation by EKLF in vitro [2].
• Skin from both Gata-3-/- and previously characterized barrier-deficient Kruppel-like factor 4-/- newborns up-regulate antimicrobial peptides, effectors of innate immunity [10].

Anatomical context of KLF1

• Transcriptional profiling studies identified the Kruppel-like factor (KLF)2 as being inhibited by the inflammatory cytokine interleukin-1beta and induced by laminar shear stress in cultured human umbilical vein endothelial cells [11].
• The AHSP promoter was transactivated by EKLF in K562 cells, which lack EKLF [12].
• Taken together, we identify EKLF as a transcription factor in macrophages able to regulate IL-12 p40 transcription depending on the cellular activation status [13].
• The expression of hEKLF is restricted to fetal liver and adult bone marrow [14].
• Human EKLF is expressed in bone marrow and HEL, JK1, and OCIM1 erythroleukemic cell lines but not in K562 nor in myeloid or lymphoid cell lines [3].

Associations of KLF1 with chemical compounds

• First, in vivo analyses implicate serine/threonine kinases as important players in the terminal differentiation of MEL cells, and demonstrate that EKLF is phosphorylated at serine and threonine residues within its transactivation region [15].
• First, green fluorescent protein or pyruvate kinase was fused to EKLF domains, and localization was monitored and quantitated by confocal microscopy [16].
• EKLF/KLF-1 is a 358-amino acid nuclear protein with an amino-terminal proline-rich domain and a carboxyl-terminal DNA binding domain [17].
• EKLF/KLF-1 containing histidine to alanine mutations that disrupt the structure of all three fingers retains appropriate nuclear localization, indicating that neither the tertiary structure of the zinc fingers nor specific DNA binding are necessary for nuclear localization [17].
• Cells were cotransfected with TR and/or KLF4 expression vectors and treated+/-100 nmol/L thyroid hormone (T3) [18].

Physical interactions of KLF1

• Remodeling is achieved with only the BRG1-BAF155 minimal complex and the EKLF zinc finger DBD, whereas transcription requires, in addition, an activation domain [2].

Regulatory relationships of KLF1

• Our results further indicate that in hematopoietic progenitors, EKLF influences chromatin organization at the human beta-globin locus and is instrumental for human beta-gene potentiation [19].

Other interactions of KLF1

• Under our conditions, the transcripts encoding KLF1 and KLF9 were never detected [20].
• Initially, 21 human proteins that have close sequence similarity to EKLF/KLF1, a known regulator of the human beta-globin gene, were identified [21].
• Competition between Sp1 and a Krüppel-like factor for GC-rich sites has been previously reported, but this is the first description of an elaborate tripartite cooperation of two Krüppel-like factors and CREB as a key step in such a competition [22].
• The first 47 amino acids of the acidic region are nearly identical to the amino-terminal portion of another Krüppel-like factor, the so-called core promoter-binding protein (CPBP) or Zf9 [23].
• The core promoter of RH50 gene was located within 68bp length from the translation start position, which included an inverse GATA motif, although obvious motifs for Sp1 or erythroid Krüppel-like factor were lacking [24].

Analytical, diagnostic and therapeutic context of KLF1

• Nevertheless, EKLF binds this atypical site by gel mobility shift assay, specifically occupies the AHSP promoter in vivo in a chromatin immunoprecipitation assay, and transactivates AHSP through this CACC site in promoter-reporter assays [1].
• The genomic locus of hEKLF was mapped to chromosomal band 19p13.12-p13.13, using fluorescence in situ hybridization [14].
• In addition, a gel mobility shift assay was used to demonstrate that GATA-1, a major erythroid transcription factor normally present at high levels in HEL cells is downregulated after treatment with PMA [25].
• Sp/KLF proteins are also potential targets for cancer chemotherapy [26].
• Sequence analysis of the hypersensitive site cores of locus control region and of the genes coding for the transcription factors erythroid Kruppel-like factor and nuclear factor (erythroid-derived 2) were normal. beta-globin mRNA levels determined by real-time polymerase chain reaction were reduced in both types of beta-like carriers [27].

References