Klf2 (lung Krueppel-like factor, LKLF) is a C2H2 zinc-finger transcription factor of the Krueppel-like factor family. Three C-terminal zinc fingers bind CACCC/GC-rich elements in RNA polymerase II promoters, and an N-terminal transactivation region recruits coactivators such as CBP/p300; the protein is nuclear and is degraded after WWP1-mediated ubiquitination. Klf2 mainly activates transcription of its targets, for example the cytosolic phospholipase A2 (Pla2g4a) promoter in rat lung epithelial cells, the endothelial nitric oxide synthase gene, the S1pr1 gene in T cells and embryonic beta-like globin genes, and it represses some genes such as VEGFA. It is expressed in lung, endothelium, lymphocytes and erythroid cells. In endothelium its expression is induced by laminar flow and lowered by inflammatory cytokines, and it promotes a quiescent, anti-inflammatory and anti-thrombotic phenotype. In cardiac myocytes it is an immediate-early gene induced by endothelin-1 and H2O2. In mouse, Klf2 is required for blood vessel stabilization (tunica media formation), primitive erythropoiesis, late lung development and T-cell egress from the thymus.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of RNA polymerase II transcription (e.g. VEGFA promoter repression in human endothelial cells). Reason: Human KLF2 binds and represses the VEGFA promoter (source of this transfer) and dampens cytokine induction of VCAM1/E-selectin. Repression is real but context-specific; activation is the predominant mode. Supporting Evidence: PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. PMID:15136591 KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of RNA polymerase II transcription (e.g. VEGFA promoter repression in human endothelial cells). Reason: Human KLF2 binds and represses the VEGFA promoter (source of this transfer) and dampens cytokine induction of VCAM1/E-selectin. Repression is real but context-specific; activation is the predominant mode. Supporting Evidence: PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. PMID:15136591 KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. |
| GO:0000785 chromatin | IEA GO_REF:0000107 | ACCEPT | Summary: Chromatin association, consistent with promoter-bound transcription factor activity. Reason: A transcription factor that binds promoter elements in cells (rat cPLA2 promoter; orthologue S1pr1 and VEGFA promoters) is located on chromatin when active. Transferred from human KLF2 (ISA and IMP sources); sound. Supporting Evidence: PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. |
| GO:0000785 chromatin | ISO GO_REF:0000121 | ACCEPT | Summary: Chromatin association, consistent with promoter-bound transcription factor activity. Reason: A transcription factor that binds promoter elements in cells (rat cPLA2 promoter; orthologue S1pr1 and VEGFA promoters) is located on chromatin when active. Transferred from human KLF2 (ISA and IMP sources); sound. Supporting Evidence: PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. |
| GO:0000902 cell morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of or within cell morphogenesis (abnormal primitive erythrocyte shape in Klf2-/- yolk sac). Reason: Phenotype-based mouse IMP from PMID:15947087 (irregular primitive red cells); mouse vascular smooth muscle cells are also cuboidal in Klf2-/- aortae. Peripheral developmental consequence. Supporting Evidence: PMID:15947087 Taken together, these experiments suggest that KLF2 is required for the final stages of maturation and/or the stability of mature primitive red blood cells. PMID:9367982 vascular smooth muscle cells in the aortae from the LKLF-/- animals displayed a cuboidal morphology and failed to organize into a compact tunica media. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: Sequence-specific binding to RNA polymerase II cis-regulatory promoter elements (CACCC/GC boxes). Reason: Rat GST-LKLF binds a GC-rich element of the cPLA2 promoter at -37/-30 by EMSA; orthologues bind CACCC boxes of the beta-globin and S1pr1 promoters. Core DNA-binding function of the zinc-finger domain. Supporting Evidence: PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: RNA polymerase II-specific DNA-binding transcription factor activity; core activity of Klf2. Reason: Klf2 is a three-finger C2H2 Krueppel-like factor that binds CACCC/GC-rich promoter elements and activates RNA polymerase II transcription. In rat lung epithelial cells LKLF binds the proximal cPLA2 promoter and activates it; orthologue studies show the same for S1pr1, eNOS and embryonic globin genes. The IBA node placement within the KLF clade is sound. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: RNA polymerase II-specific DNA-binding transcription factor activity; core activity of Klf2. Reason: Klf2 is a three-finger C2H2 Krueppel-like factor that binds CACCC/GC-rich promoter elements and activates RNA polymerase II transcription. In rat lung epithelial cells LKLF binds the proximal cPLA2 promoter and activates it; orthologue studies show the same for S1pr1, eNOS and embryonic globin genes. The IBA node placement within the KLF clade is sound. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISO GO_REF:0000121 | ACCEPT | Summary: RNA polymerase II-specific DNA-binding transcription factor activity; core activity of Klf2. Reason: Klf2 is a three-finger C2H2 Krueppel-like factor that binds CACCC/GC-rich promoter elements and activates RNA polymerase II transcription. In rat lung epithelial cells LKLF binds the proximal cPLA2 promoter and activates it; orthologue studies show the same for S1pr1, eNOS and embryonic globin genes. The IBA node placement within the KLF clade is sound. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 |
| GO:0001701 in utero embryonic development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of or within in utero embryonic development (Klf2-/- embryonic lethality). Reason: Klf2-/- mouse embryos die at E12.5-E14.5 from hemorrhage; necessity phenotype, non-core. Supporting Evidence: PMID:9367982 LKLF-/- embryos died between E12.5 and E14.5 from severe intra-embryonic and intra-amniotic hemorrhaging. |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: Generic DNA binding; true but less specific than the supported promoter-element binding. Reason: Klf2 binds specific RNA polymerase II cis-regulatory elements; GO:0000978 (already carried by the IBA row) is an is_a descendant of GO:0003677 (checked with OAK) and is the precise supported term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0003677 DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: Generic DNA binding; true but less specific than the supported promoter-element binding. Reason: Klf2 binds specific RNA polymerase II cis-regulatory elements; GO:0000978 (already carried by the IBA row) is an is_a descendant of GO:0003677 (checked with OAK) and is the precise supported term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS TRANSFER Human KLF2 binds promoter DNA; transfer sound, term too general. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | MODIFY | Summary: DNA-binding transcription factor activity; correct, but the activity is RNA polymerase II-specific. Reason: Klf2 regulates RNA polymerase II promoters (cPLA2 in rat; eNOS, S1pr1, globins in orthologues). GO:0000981 is an is_a descendant of GO:0003700 (OAK) and is already carried by IBA/IEA/ISO rows. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000121 | MODIFY | Summary: DNA-binding transcription factor activity; correct, but the activity is RNA polymerase II-specific. Reason: Klf2 regulates RNA polymerase II promoters (cPLA2 in rat; eNOS, S1pr1, globins in orthologues). GO:0000981 is an is_a descendant of GO:0003700 (OAK) and is already carried by IBA/IEA/ISO rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342772 SUPPORTS TRANSFER Orthologue TF activity transfers correctly; only the term is too general. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000121 | MODIFY | Summary: DNA-binding transcription factor activity; correct, but the activity is RNA polymerase II-specific. Reason: Klf2 regulates RNA polymerase II promoters (cPLA2 in rat; eNOS, S1pr1, globins in orthologues). GO:0000981 is an is_a descendant of GO:0003700 (OAK) and is already carried by IBA/IEA/ISO rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS TRANSFER Orthologue TF activity transfers correctly; only the term is too general. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter |
| GO:0003700 DNA-binding transcription factor activity | ISS GO_REF:0000024 | MODIFY | Summary: DNA-binding transcription factor activity; correct, but the activity is RNA polymerase II-specific. Reason: Klf2 regulates RNA polymerase II promoters (cPLA2 in rat; eNOS, S1pr1, globins in orthologues). GO:0000981 is an is_a descendant of GO:0003700 (OAK) and is already carried by IBA/IEA/ISO rows. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS TRANSFER Orthologue TF activity transfers correctly; only the term is too general. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization of a sequence-specific transcription factor. Reason: Klf2 acts on promoter DNA and is nuclear (UniProt, by similarity); the IBA, IEA and ISO rows agree. Nucleus is the site of its core activity. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt SUBCELLULAR LOCATION: Nucleus PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization of a sequence-specific transcription factor. Reason: Klf2 acts on promoter DNA and is nuclear (UniProt, by similarity); the IBA, IEA and ISO rows agree. Nucleus is the site of its core activity. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt SUBCELLULAR LOCATION: Nucleus PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: Nuclear localization of a sequence-specific transcription factor. Reason: Klf2 acts on promoter DNA and is nuclear (UniProt, by similarity); the IBA, IEA and ISO rows agree. Nucleus is the site of its core activity. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt SUBCELLULAR LOCATION: Nucleus PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | MODIFY | Summary: Regulation of RNA polymerase II transcription; correct but general. Reason: Klf2 activates most of its characterised targets (GO:0045944) and represses some (VEGFA; GO:0000122). Both are is_a descendants of GO:0006357 (OAK) and both are carried by other rows of this gene, so the IBA is refined to both. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1306780 SUPPORTS TRANSFER KLF-clade transcriptional regulation transfers; term refined to the signed descendants. MGI:MGI:1333796 SUPPORTS TRANSFER KLF-clade transcriptional regulation transfers; term refined to the signed descendants. MGI:MGI:1333856 SUPPORTS TRANSFER KLF-clade transcriptional regulation transfers; term refined to the signed descendants. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. |
| GO:0010467 gene expression | ISO GO_REF:0000121 | MODIFY | Summary: Acts upstream of or within gene expression (mouse ES-cell lincRNA knockdown screen). Reason: The source (PMID:21874018) is a high-throughput ES-cell knockdown readout; 'gene expression' is uninformative for a sequence-specific transcription factor. Its effect on gene expression is through activation of RNA polymerase II transcription (lateral refinement to the regulation term). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342772 SUPPORTS TRANSFER Mouse knockdown effect transfers; term refined. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15947087 In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic Ξ΅-globin gene but not the adult Ξ²-globin gene |
| GO:0032715 negative regulation of interleukin-6 production | IMP PMID:19192484 Endothelin-1 regulation of immediate early gene expression i... | KEEP AS NON CORE | Summary: Negative regulation of IL-6 production in endothelin-1-stimulated rat cardiac myocytes (IMP). Reason: Only the title and bibliographic record are cached; the title states negative feedback regulation of IL-6 by Atf3 and Klf2, consistent with the curator's IMP. Deferring to the curator who read the full text; KLF2 anti-inflammatory gene regulation is well established in endothelium. Peripheral to the core activity. Supporting Evidence: PMID:19192484 negative feedback regulation of interleukin 6 by Atf3 and Klf2 PMID:15136591 KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. |
| GO:0034101 erythrocyte homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of or within erythrocyte homeostasis (anemia in Klf2-/- embryos). Reason: Klf2-/- embryos are anemic with apoptotic primitive erythroid cells; phenotype downstream of embryonic globin gene regulation. Supporting Evidence: PMID:15947087 They also display growth retardation and anemia. PMID:15947087 Taken together, these experiments suggest that KLF2 is required for the final stages of maturation and/or the stability of mature primitive red blood cells. |
| GO:0034616 response to laminar fluid shear stress | IEP PMID:16466697 Shear stress regulation of KrΓΌppel-like factor 2 expression ... | MODIFY | Summary: Response to laminar fluid shear stress (IEP; flow-pattern-specific KLF2 expression, including a rat aortic model). Reason: The study measures KLF2 expression in endothelial cells under different flow patterns, a cellular response. GO:0071499 cellular response to laminar fluid shear stress is an is_a descendant of GO:0034616 (OAK) and is carried by other rows of this gene; the IEP evidence is expression-based, so the row is non-core. Proposed replacements: cellular response to laminar fluid shear stress Supporting Evidence: PMID:16466697 pulsatile flow with a significant forward direction induced sustained expression of KLF2 in cultured ECs |
| GO:0035264 multicellular organism growth | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of or within multicellular organism growth (growth retardation of Klf2-/- embryos). Reason: Growth retardation is a secondary phenotype (likely due to anemia and hemorrhage); non-core. Supporting Evidence: PMID:15947087 They also display growth retardation and anemia. |
| GO:0040029 epigenetic regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Acts upstream of or within epigenetic regulation of gene expression (Prdm14-Klf2 reprogramming of epiblast stem cells). Reason: Forced Prdm14-Klf2 expression accelerates reversion of epiSCs to naive pluripotency with DNA demethylation and X reactivation; these epigenetic changes are consequences of a cell-state transition in an overexpression system, not an activity of Klf2, which has no chromatin-modifying function. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1342772 SUPPORTS SOURCE BUT NOT TARGET Overexpression reprogramming phenotype; indirect. Supporting Evidence: PMID:22482507 Reprogramming of epiSCs by the combinatorial effect of Prdm14-Klf2 involves key epigenetic changes |
| GO:0042311 vasodilation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of vasodilation, via eNOS induction. Reason: KLF2 induces eNOS expression and activity in endothelial cells; the vasodilatory effect is downstream of its transcriptional activity, consistent with the acts_upstream_of qualifier. Supporting Evidence: PMID:15136591 Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. |
| GO:0043249 erythrocyte maturation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of or within erythrocyte maturation (primitive erythroid cells). Reason: Klf2 is required for final maturation and/or stability of primitive red cells in mouse; non-core developmental role. Supporting Evidence: PMID:15947087 Taken together, these experiments suggest that KLF2 is required for the final stages of maturation and/or the stability of mature primitive red blood cells. |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of positive regulation of nitric oxide biosynthesis (eNOS induction). Reason: KLF2 transcriptionally induces NOS3, increasing NO synthase activity; indirect (acts_upstream_of) and peripheral to the core activity. Supporting Evidence: PMID:15136591 Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000120 | MODIFY | Summary: Positive regulation of DNA-templated transcription; correct but the targets are RNA polymerase II promoters. Reason: GO:0045944 is an is_a descendant of GO:0045893 (OAK). For the rat IMP row (PMID:15540987) the regulated promoter is the RNA polymerase II-transcribed cPLA2 (Pla2g4a) gene, so the specific term fits the experiment. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:15540987 Lung KrΓΌppel-like factor (LKLF) is a transcriptional activat... | MODIFY | Summary: Positive regulation of DNA-templated transcription; correct but the targets are RNA polymerase II promoters. Reason: GO:0045944 is an is_a descendant of GO:0045893 (OAK). For the rat IMP row (PMID:15540987) the regulated promoter is the RNA polymerase II-transcribed cPLA2 (Pla2g4a) gene, so the specific term fits the experiment. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0045893 positive regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: Positive regulation of DNA-templated transcription; correct but the targets are RNA polymerase II promoters. Reason: GO:0045944 is an is_a descendant of GO:0045893 (OAK). For the rat IMP row (PMID:15540987) the regulated promoter is the RNA polymerase II-transcribed cPLA2 (Pla2g4a) gene, so the specific term fits the experiment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342772 SUPPORTS TRANSFER Orthologue activator function transfers; term refined to RNA polymerase II. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0045893 positive regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: Positive regulation of DNA-templated transcription; correct but the targets are RNA polymerase II promoters. Reason: GO:0045944 is an is_a descendant of GO:0045893 (OAK). For the rat IMP row (PMID:15540987) the regulated promoter is the RNA polymerase II-transcribed cPLA2 (Pla2g4a) gene, so the specific term fits the experiment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS TRANSFER Orthologue activator function transfers; term refined to RNA polymerase II. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0045893 positive regulation of DNA-templated transcription | ISS GO_REF:0000024 | MODIFY | Summary: Positive regulation of DNA-templated transcription; correct but the targets are RNA polymerase II promoters. Reason: GO:0045944 is an is_a descendant of GO:0045893 (OAK). For the rat IMP row (PMID:15540987) the regulated promoter is the RNA polymerase II-transcribed cPLA2 (Pla2g4a) gene, so the specific term fits the experiment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS TRANSFER Orthologue activator function transfers; term refined to RNA polymerase II. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Positive regulation of RNA polymerase II transcription; core process for Klf2. Reason: Rat LKLF activates the cPLA2 promoter and its knockdown lowers basal cPLA2 expression; mouse Klf2 is required for embryonic beta-like globin expression and activates the S1pr1 promoter; human KLF2 induces eNOS. Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased PMID:15947087 In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic Ξ΅-globin gene but not the adult Ξ²-globin gene PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: Positive regulation of RNA polymerase II transcription; core process for Klf2. Reason: Rat LKLF activates the cPLA2 promoter and its knockdown lowers basal cPLA2 expression; mouse Klf2 is required for embryonic beta-like globin expression and activates the S1pr1 promoter; human KLF2 induces eNOS. Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased PMID:15947087 In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic Ξ΅-globin gene but not the adult Ξ²-globin gene PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: Positive regulation of RNA polymerase II transcription; core process for Klf2. Reason: Rat LKLF activates the cPLA2 promoter and its knockdown lowers basal cPLA2 expression; mouse Klf2 is required for embryonic beta-like globin expression and activates the S1pr1 promoter; human KLF2 induces eNOS. Supporting Evidence: PMID:15540987 We report the identification of LKLF (lung KLF; KLF-2) as a transcriptional activator of cPLA 2 , which binds to the proximal region of the cPLA 2 promoter PMID:15540987 Concomitantly, basal expression of cPLA 2 in these clones was markedly decreased PMID:15947087 In mice carrying the entire human globin locus, KLF2 also regulates the expression of the human embryonic Ξ΅-globin gene but not the adult Ξ²-globin gene PMID:16855590 KLF2 both binds and transactivates the promoter for S1P1 |
| GO:0048386 positive regulation of retinoic acid receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of retinoic acid receptor signaling, via modulation of RARA binding to RAREs (human data). Reason: Human KLF2 IDA (CACAO) supports an effect on RARA-dependent signaling; UniProt states this only as a possibility. Plausible, peripheral to the core transcription-factor activity. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Might be involved in transcriptional regulation by modulating the binding of the RARA nuclear receptor to RARE DNA elements |
| GO:0048386 positive regulation of retinoic acid receptor signaling pathway | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of retinoic acid receptor signaling, via modulation of RARA binding to RAREs (human data). Reason: Human KLF2 IDA (CACAO) supports an effect on RARA-dependent signaling; UniProt states this only as a possibility. Plausible, peripheral to the core transcription-factor activity. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Might be involved in transcriptional regulation by modulating the binding of the RARA nuclear receptor to RARE DNA elements |
| GO:0051247 positive regulation of protein metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of protein metabolic process; source is a human IGI from a KLF4/Erk5 endothelial study. Reason: The source paper (PMID:20551324) is about Erk5-induced KLF4; any KLF2 effect on protein levels is an indirect consequence of target-gene transcription, captured by GO:0045944. Klf2 is not shown to regulate protein metabolism (synthesis or turnover) as such. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0051247 positive regulation of protein metabolic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of protein metabolic process; source is a human IGI from a KLF4/Erk5 endothelial study. Reason: The source paper (PMID:20551324) is about Erk5-induced KLF4; any KLF2 effect on protein levels is an indirect consequence of target-gene transcription, captured by GO:0045944. Klf2 is not shown to regulate protein metabolism (synthesis or turnover) as such. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q9Y5W3 SUPPORTS SOURCE BUT NOT TARGET Source annotation is an indirect, uninformative readout of transcriptional activity. Supporting Evidence: file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:0060509 type I pneumocyte differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts upstream of or within type I pneumocyte differentiation (Klf2-null ES-cell chimeras). Reason: Mouse chimera studies show LKLF is needed for normal late lung development; developmental phenotype downstream of the transcription factor. Supporting Evidence: PMID:10409672 These studies show that LKLF plays an important role in normal lung development. |
| GO:0070301 cellular response to hydrogen peroxide | IEP PMID:18406357 Differential regulation of KrΓΌppel-like factor family transc... | KEEP AS NON CORE | Summary: Cellular response to hydrogen peroxide: H2O2 transiently induces Klf2 mRNA in rat cardiac myocytes (ERK1/2-dependent). Reason: Expression-only (IEP) evidence from full text; acceptable as a response term, not a core function. Supporting Evidence: PMID:18406357 H2O2 (0.2 mM) promotes cardiac myocyte apoptosis [41], but also stimulates ERK1/2 (and other pathways) [42], and stimulated a transient increase in expression of Klf2 (Fig. 5A). |
| GO:0071347 cellular response to interleukin-1 | IEP PMID:18406357 Differential regulation of KrΓΌppel-like factor family transc... | KEEP AS NON CORE | Summary: Cellular response to interleukin-1: IL-1beta rapidly downregulates Klf2 mRNA in rat cardiac myocytes. Reason: Expression-only (IEP); consistent with cytokine repression of KLF2 in endothelium. Non-core. Supporting Evidence: PMID:18406357 IL-1Ξ² or TNFΞ± profoundly and rapidly (from βΌ 1 h) downregulated Klf2 mRNA expression, a response which was sustained over at least 6 h (Fig. 6, A and B). |
| GO:0071356 cellular response to tumor necrosis factor | IEP PMID:18406357 Differential regulation of KrΓΌppel-like factor family transc... | KEEP AS NON CORE | Summary: Cellular response to tumor necrosis factor: TNFalpha downregulates Klf2 mRNA in rat cardiac myocytes. Reason: Expression-only (IEP); non-core. Supporting Evidence: PMID:18406357 IL-1Ξ² or TNFΞ± profoundly and rapidly (from βΌ 1 h) downregulated Klf2 mRNA expression, a response which was sustained over at least 6 h (Fig. 6, A and B). |
| GO:0071498 cellular response to fluid shear stress | IEA GO_REF:0000107 | MODIFY | Summary: Cellular response to fluid shear stress; correct but the characterised response is to laminar flow. Reason: KLF2 is induced by sustained laminar/pulsatile forward flow and suppressed by oscillatory flow, and it drives the flow-dependent atheroprotective program (eNOS induction). GO:0071499 is an is_a descendant of GO:0071498 (OAK) and is already carried by this gene. Proposed replacements: cellular response to laminar fluid shear stress Supporting Evidence: PMID:12176889 To date LKLF is the first endothelial transcription factor that is uniquely induced by flow PMID:16466697 pulsatile flow with a significant forward direction induced sustained expression of KLF2 in cultured ECs PMID:15136591 Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. |
| GO:0071498 cellular response to fluid shear stress | ISO GO_REF:0000121 | MODIFY | Summary: Cellular response to fluid shear stress; correct but the characterised response is to laminar flow. Reason: KLF2 is induced by sustained laminar/pulsatile forward flow and suppressed by oscillatory flow, and it drives the flow-dependent atheroprotective program (eNOS induction). GO:0071499 is an is_a descendant of GO:0071498 (OAK) and is already carried by this gene. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS TRANSFER Human KLF2 flow response transfers; refined to laminar flow. Proposed replacements: cellular response to laminar fluid shear stress Supporting Evidence: PMID:12176889 To date LKLF is the first endothelial transcription factor that is uniquely induced by flow PMID:16466697 pulsatile flow with a significant forward direction induced sustained expression of KLF2 in cultured ECs PMID:15136591 Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. |
| GO:0071499 cellular response to laminar fluid shear stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cellular response to laminar fluid shear stress; KLF2 is the endothelial transcription factor most specifically induced by laminar flow. Reason: KLF2 is induced by laminar flow and mediates part of the endothelial flow response (eNOS induction, anti-inflammatory phenotype); a rat aortic model shows flow-associated KLF2 patterns. Characteristic physiological context of the core transcription-factor activity, but not the activity itself. Supporting Evidence: PMID:12176889 To date LKLF is the first endothelial transcription factor that is uniquely induced by flow PMID:16466697 pulsatile flow with a significant forward direction induced sustained expression of KLF2 in cultured ECs PMID:15136591 Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. |
| GO:0071499 cellular response to laminar fluid shear stress | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cellular response to laminar fluid shear stress; KLF2 is the endothelial transcription factor most specifically induced by laminar flow. Reason: KLF2 is induced by laminar flow and mediates part of the endothelial flow response (eNOS induction, anti-inflammatory phenotype); a rat aortic model shows flow-associated KLF2 patterns. Characteristic physiological context of the core transcription-factor activity, but not the activity itself. Supporting Evidence: PMID:12176889 To date LKLF is the first endothelial transcription factor that is uniquely induced by flow PMID:16466697 pulsatile flow with a significant forward direction induced sustained expression of KLF2 in cultured ECs PMID:15136591 Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. |
| GO:0097533 cellular stress response to acid chemical | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cellular stress response to acid chemical; transferred from a human uric-acid / miR-92a angiogenesis study. Reason: In the source study (PMID:26299712) high uric acid lowers miR-92a, raising KLF2, which represses VEGFA. KLF2 is a downstream transcriptional effector in one experimental context; framing it as part of a stress response to acid anions overstates its role. Its activity is captured by GO:0000122 and GO:1903671. Supporting Evidence: PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. |
| GO:0097533 cellular stress response to acid chemical | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Cellular stress response to acid chemical; transferred from a human uric-acid / miR-92a angiogenesis study. Reason: In the source study (PMID:26299712) high uric acid lowers miR-92a, raising KLF2, which represses VEGFA. KLF2 is a downstream transcriptional effector in one experimental context; framing it as part of a stress response to acid anions overstates its role. Its activity is captured by GO:0000122 and GO:1903671. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS SOURCE BUT NOT TARGET Single-context human study; stress-response framing is an over-reading. Supporting Evidence: PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. |
| GO:1903671 negative regulation of sprouting angiogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of sprouting angiogenesis (via VEGFA repression in human endothelial cells). Reason: Human KLF2 represses VEGFA and its knockdown relieves uric-acid-mediated inhibition of angiogenesis in vitro. Downstream physiological role of the transcription factor. Supporting Evidence: PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. |
| GO:1903671 negative regulation of sprouting angiogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of sprouting angiogenesis (via VEGFA repression in human endothelial cells). Reason: Human KLF2 represses VEGFA and its knockdown relieves uric-acid-mediated inhibition of angiogenesis in vitro. Downstream physiological role of the transcription factor. Supporting Evidence: PMID:26299712 KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: Sequence-specific double-stranded DNA binding; correct but more general than the supported RNA polymerase II cis-regulatory binding. Reason: GO:0000978 is an is_a descendant of GO:1990837 (checked with OAK) and is supported by rat EMSA binding to the cPLA2 promoter. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:1990837 sequence-specific double-stranded DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: Sequence-specific double-stranded DNA binding; correct but more general than the supported RNA polymerase II cis-regulatory binding. Reason: GO:0000978 is an is_a descendant of GO:1990837 (checked with OAK) and is supported by rat EMSA binding to the cPLA2 promoter. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9Y5W3 SUPPORTS TRANSFER Human KLF2 sequence-specific DNA binding transfers; only the term is too general. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:15540987 LKLF bound to a GC-rich region of the cPLA2 promoter located between -37 and -30 upstream from the transcription start site file:rat/Klf2/Klf2-uniprot.txt Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. |
| GO:1990859 cellular response to endothelin | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Cellular response to endothelin: Klf2 mRNA is rapidly induced (~9-fold) by endothelin-1 in neonatal rat cardiac myocytes as an immediate-early gene. Reason: Expression-based (IEP; the IEA ARBA row restates the same claim). Under GO's IEP convention the response term is acceptable, but it reflects regulation of Klf2 rather than a function of Klf2. Supporting Evidence: PMID:18406357 In response to endothelin-1, Klf2 mRNA expression was rapidly increased |
| GO:1990859 cellular response to endothelin | IEP PMID:18406357 Differential regulation of KrΓΌppel-like factor family transc... | KEEP AS NON CORE | Summary: Cellular response to endothelin: Klf2 mRNA is rapidly induced (~9-fold) by endothelin-1 in neonatal rat cardiac myocytes as an immediate-early gene. Reason: Expression-based (IEP; the IEA ARBA row restates the same claim). Under GO's IEP convention the response term is acceptable, but it reflects regulation of Klf2 rather than a function of Klf2. Supporting Evidence: PMID:18406357 In response to endothelin-1, Klf2 mRNA expression was rapidly increased |
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Download this section (compressed HTML)Q: Which rat Klf2 target genes mediate the negative feedback on IL-6 in endothelin-1-stimulated cardiac myocytes, and is the effect direct promoter repression or coactivator competition?
Q: Is rat Klf2 phosphorylation by ERK (shown in vitro by Wick et al.) required for its activation of the cPLA2 promoter downstream of oncogenic Ras?
Q: Is GO:0097533 (cellular stress response to acid chemical) an appropriate term for the uric acid / miR-92a / KLF2 axis, or should that source annotation be revised?
Experiment: ChIP-seq for endogenous Klf2 in rat cardiac myocytes after endothelin-1 stimulation, combined with Klf2 knockdown RNA-seq, to define direct targets including Il6.
Type: ChIP-seq
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