Disease relevance of KLF2

• Utilizing gene expression profiling to identify aberrantly expressed genes in ovarian cancer, we found that KLF2 was significantly and specifically downregulated in ovarian tumors [1].
• KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis [2].
• Overexpression and silencing of KLF2 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KLF2 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development [2].
• Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation [3].
• A study of the relationships between KLF2 polymorphisms and body weight control in a French population [4].

High impact information on KLF2

• Conversely, LKLF-deficient peripheral T cells produced by gene targeting showed increased proliferation, increased cell size and enhanced expression of surface activation markers in vivo [5].
• LKLF appeared to function, at least in part, by decreasing expression of the proto-oncogene encoding c-Myc [5].
• Here we show that forced expression of the lung Krüppel-like transcription factor (LKLF) in Jurkat T cells is sufficient to program a quiescent phenotype characterized by decreased proliferation, reduced cell size and protein synthesis and decreased surface expression of activation markers [5].
• Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity [6].
• In addition, KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines [6].

Biological context of KLF2

• KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo [7].
• Both activation and zinc-finger domains of KLF2 were required for this suppression of Wee1 expression [1].
• Thus, the level of WEE1 is regulated by KLF2 and enhanced KLF2 expression sensitizes cells to DNA damage-induced apoptosis [1].
• After reintroducing KLF2 into ovarian cancer cell lines, we observed decreased cell growth and increased sensitivity to DNA damage-induced apoptosis [1].
• In addition, we demonstrated that Wee1 expression prevents cancer cells from undergoing apoptosis in response to DNA damage; however, this resistance was abolished by coexpression of KLF2, which inhibits WEE1 transcription [1].

Anatomical context of KLF2

• In co-transfection assays in K562 cells, it was demonstrated that KLF2, 5 and 13 positively regulate, and KLF8 negatively regulates, the gamma-globin gene through the CACCC promoter element [8].
• Semi-quantitative RT-PCR demonstrated that all eight of these candidates are present in human erythroid cell lines, and that the expression of the KLF2, 4, 5 and 12 mRNAs changed significantly upon erythroid differentiation [8].
• Here we show, however, that KLF2 is essential for T-cell trafficking [9].
• Our findings suggest that KLF2 serves to license mature T cells for trafficking from the thymus and recirculation through secondary lymphoid tissues [9].
• Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells [10].

Associations of KLF2 with chemical compounds

• Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element-binding protein (CBP/p300) as a unifying mechanism for these various effects [6].
• This statin effect on KLF2 expression was reversed by addition of mevalonate and its downstream metabolite geranygeranyl pyrophosphate [11].
• Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of MEF2 by NF-kappaB and histone deacetylases [12].
• Up-regulation of the T cell quiescence factor KLF2 in a leukaemic T-cell line after expression of the inositol 5'-phosphatase SHIP-1 [13].
• LKLF, expressed as a glutathione S-transferase fusion protein, was capable of binding to Box B [14].

Physical interactions of KLF2

• Here, we demonstrate that WWP1 interacts with KLF2 in vivo and mediates both poly-ubiquitination and proteasomal degradation of KLF2 [15].

Regulatory relationships of KLF2

• In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic epsilon-globin gene but not the adult beta-globin gene, suggesting that this developmental-stage-specific role is evolutionarily conserved [7].
• Our experiments demonstrate for the first time that WWP1 promotes ubiquitination and degradation of KLF2 and is not involved in the ubiquitin-transfer reaction [15].
• Tumor necrosis factor alpha (TNF-alpha) potently inhibited KLF2 expression [12].
• Mechanistically, KLF2 inhibits PAR-1 expression and, as a consequence, thrombin-mediated nuclear factor kappaB (NF-kappaB) nuclear accumulation and DNA binding [16].
• Inhibition of either PI3K or AKT and depletion of AKT abrogated Ang1-induced KLF2 expression [17].

Other interactions of KLF2

• Multiple SP1/KLF family members, other than KLF2 or KLF4, were expressed in undifferentiated human ES cells [18].
• Furthermore, overexpression of KLF2 inhibited the cytokine-mediated induction of tissue factor (TF) [19].
• In mammalian cells, WWP1 functions as a cofactor by binding LKLF and suppressing transactivation [20].
• LKLF but not CYP1B1 mRNA was detected exclusively in the vascular endothelium of healthy human aorta by in situ hybridization and appeared to be flow regulated [21].
• KLF2 attenuates cell migration by affecting multiple genes including VEGFR2 and the potent antimigratory SEMA3F [22].

Analytical, diagnostic and therapeutic context of KLF2

• The presence of nucleolin on the KLF2 promoter in macrophages was verified by electrophoretic mobility shift assays [23].
• In the present study, by using DNA affinity chromatography and mass spectrometry, we have identified nucleolin as an additional protein that binds to a palindromic response region in the KLF2 promoter [23].
• Interestingly, in mouse and human endothelial cell lines, electrophoretic mobility shift assays and chromatin immunoprecipitation analyses indicated that nucleolin binds the KLF2 promoter only upon application of fluid shear stress [23].
• Dissection of the biomechanics of LKLF regulation in vitro demonstrated that steady flow and pulsatile flow induced basal LKLF expression 15- and 36-fold at shear stresses greater than approximately 5 dyne/cm2, whereas cyclic stretch had no effect [24].
• We have previously identified and isolated the mouse LKLF gene and examined its role using gene targeting [25].

References