Klf4 (Kruppel-like factor 4, GKLF) encodes a nuclear C2H2 zinc-finger transcription factor of the KLF family. Its three C-terminal zinc fingers bind GC-rich/CACCC elements in RNA polymerase II promoters, and its N-terminal region mediates transcriptional activation or repression in a target- and context-dependent manner, partly through the coactivator p300 and the corepressor HDAC2, which acetylate and deacetylate KLF4 respectively. In rat, KLF4 activates the laminin gamma1 (with Sp1), p53 and SM22alpha promoters and assembles with CREB and p53 on the bradykinin B2 receptor enhancer, and it represses RARalpha and PDGFRbeta. Its best-characterised role is growth inhibition of vascular smooth muscle cells via induction of p53/p21 and attenuation of PDGFR-PI3K/ERK signalling, limiting neointima formation. Klf4 is an immediate-early gene induced by endothelin-1, oxidative stress, retinoic acid and PDGF-BB. Orthologous data from mouse and human establish further roles in epidermal barrier formation, pluripotency (as a reprogramming factor) and endothelial anti-inflammatory gene expression.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: KLF4 represses Pol II target genes, e.g. RARA in rat VSMCs and SMC differentiation marker genes in mouse SMCs, by binding their regulatory regions. Reason: Core process; directly supported by promoter-binding and repression data. Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 represses Pol II target genes, e.g. RARA in rat VSMCs and SMC differentiation marker genes in mouse SMCs, by binding their regulatory regions. Reason: Core process; directly supported by promoter-binding and repression data. Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0000785 chromatin | IDA PMID:15632413 Combinatorial control of the bradykinin B2 receptor promoter... | ACCEPT | Summary: KLF4 occupies chromatin at target promoters (B2R enhancer in rat kidney; SMC marker promoters). Reason: Directly supported by ChIP in rat and mouse; location where the core activity occurs. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation PMID:12970361 results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin |
| GO:0000785 chromatin | IEA GO_REF:0000107 | ACCEPT | Summary: KLF4 occupies chromatin at target promoters (B2R enhancer in rat kidney; SMC marker promoters). Reason: Directly supported by ChIP in rat and mouse; location where the core activity occurs. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation PMID:12970361 results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin |
| GO:0000785 chromatin | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 occupies chromatin at target promoters (B2R enhancer in rat kidney; SMC marker promoters). Reason: Directly supported by ChIP in rat and mouse; location where the core activity occurs. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation PMID:12970361 results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin |
| GO:0000791 euchromatin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Euchromatin localization transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with active-promoter occupancy; non-core refinement of chromatin. |
| GO:0000791 euchromatin | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Euchromatin localization transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with active-promoter occupancy; non-core refinement of chromatin. |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:19531492 KrΓΌppel-like factor 4 inhibits proliferation by platelet-der... | MODIFY | Summary: KLF4 binds cis-regulatory regions of Pol II-transcribed genes (RARA 5' region, SM22alpha, LAMC1, p21) in a sequence-specific manner through its three C2H2 zinc fingers. Reason: Correct but general. The rat evidence (ChIP and oligonucleotide pull-down at defined CACCC/GT-box elements of Pol II promoters) supports the more specific descendant GO:0000978, which the gene already carries. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 binds cis-regulatory regions of Pol II-transcribed genes (RARA 5' region, SM22alpha, LAMC1, p21) in a sequence-specific manner through its three C2H2 zinc fingers. Reason: Correct but general. The rat evidence (ChIP and oligonucleotide pull-down at defined CACCC/GT-box elements of Pol II promoters) supports the more specific descendant GO:0000978, which the gene already carries. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0000976 transcription cis-regulatory region binding | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 binds cis-regulatory regions of Pol II-transcribed genes (RARA 5' region, SM22alpha, LAMC1, p21) in a sequence-specific manner through its three C2H2 zinc fingers. Reason: Correct but general. The rat evidence (ChIP and oligonucleotide pull-down at defined CACCC/GT-box elements of Pol II promoters) supports the more specific descendant GO:0000978, which the gene already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Sequence-specific binding of GC-rich/CACCC elements in Pol II cis-regulatory regions by the three C-terminal C2H2 zinc fingers is the core DNA-binding activity of KLF4. Reason: Directly supported in rat by ChIP/pull-down at defined KLF sites of the SM22alpha promoter and binding to the RARA regulatory region; family-level mechanism is well established. Supporting Evidence: PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISO GO_REF:0000121 | ACCEPT | Summary: Sequence-specific binding of GC-rich/CACCC elements in Pol II cis-regulatory regions by the three C-terminal C2H2 zinc fingers is the core DNA-binding activity of KLF4. Reason: Directly supported in rat by ChIP/pull-down at defined KLF sites of the SM22alpha promoter and binding to the RARA regulatory region; family-level mechanism is well established. Supporting Evidence: PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISO GO_REF:0000121 | ACCEPT | Summary: Sequence-specific binding of GC-rich/CACCC elements in Pol II cis-regulatory regions by the three C-terminal C2H2 zinc fingers is the core DNA-binding activity of KLF4. Reason: Directly supported in rat by ChIP/pull-down at defined KLF sites of the SM22alpha promoter and binding to the RARA regulatory region; family-level mechanism is well established. Supporting Evidence: PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 is a sequence-specific Pol II transcription factor that activates some targets (p53, p21, LAMC1, SM22alpha) and represses others (RARA, SMC marker genes). Reason: Correct but general; both specific descendants are supported (activator: p53/LAMC1 promoter activation; repressor: RARA and SMC marker repression), so both are listed. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 is a sequence-specific Pol II transcription factor that activates some targets (p53, p21, LAMC1, SM22alpha) and represses others (RARA, SMC marker genes). Reason: Correct but general; both specific descendants are supported (activator: p53/LAMC1 promoter activation; repressor: RARA and SMC marker repression), so both are listed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term, so both Pol II activator and repressor terms are proposed Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0001221 transcription coregulator binding | IPI PMID:21252119 ATRA activates and PDGF-BB represses the SM22Ξ± promoter thro... | KEEP AS NON CORE | Summary: KLF4 interacts with the acetyltransferase coactivator p300 and with HDAC2 at the SM22alpha promoter; acetylation status controls which site KLF4 occupies. Reason: IPI supported by the cited rat VSMC study; coregulator binding is part of how KLF4 regulates transcription but is not its defining activity. Supporting Evidence: PMID:21252119 ATRA stimulated KLF4 acetylation by inducing KLF4 phosphorylation and increasing its interaction with p300 |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:17659301 Induction of p53 by GKLF is essential for inhibition of prol... | ACCEPT | Summary: KLF4 activates Pol II promoters by binding cis-elements; in rat VSMCs it activates the p53 promoter and in mesangial cells the LAMC1 promoter (in synergy with Sp1). Reason: Core activity with direct rat evidence (reporter assays with intact activation and DNA-binding domains). Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000120 | ACCEPT | Summary: KLF4 activates Pol II promoters by binding cis-elements; in rat VSMCs it activates the p53 promoter and in mesangial cells the LAMC1 promoter (in synergy with Sp1). Reason: Core activity with direct rat evidence (reporter assays with intact activation and DNA-binding domains). Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 activates Pol II promoters by binding cis-elements; in rat VSMCs it activates the p53 promoter and in mesangial cells the LAMC1 promoter (in synergy with Sp1). Reason: Core activity with direct rat evidence (reporter assays with intact activation and DNA-binding domains). Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 activates Pol II promoters by binding cis-elements; in rat VSMCs it activates the p53 promoter and in mesangial cells the LAMC1 promoter (in synergy with Sp1). Reason: Core activity with direct rat evidence (reporter assays with intact activation and DNA-binding domains). Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0002357 defense response to tumor cell | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Defense response to tumor cell transferred from ortholog data. Reason: The term describes an immune defence process against tumour cells. KLF4's tumour-suppressive effects are cell-intrinsic growth control by a transcription factor, which this term does not capture; likely an over-interpretation. |
| GO:0002357 defense response to tumor cell | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Defense response to tumor cell transferred from ortholog data. Reason: The term describes an immune defence process against tumour cells. KLF4's tumour-suppressive effects are cell-intrinsic growth control by a transcription factor, which this term does not capture; likely an over-interpretation. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:O43474 Β· human KLF4 UNRESOLVED source annotation not inspected here; KLF4 tumour suppression is cell-intrinsic growth control, not the immune defence process this term describes |
| GO:0003690 double-stranded DNA binding | IDA PMID:12034813 Synergistic activation of the rat laminin gamma1 chain promo... | MODIFY | Summary: Rat GKLF was cloned by yeast one-hybrid with the bcn-1 element and binds this double-stranded GC/GT-rich element. Reason: Correct but uninformative; binding is to a specific cis-regulatory element of a Pol II gene, so the specific term GO:0000978 (already carried) is preferred. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12034813 We show that GKLF binds bcn-1, but this binding is not required for the GKLF-mediated activation of the LAMC1 promoter. |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:12034813 Synergistic activation of the rat laminin gamma1 chain promo... | MODIFY | Summary: KLF4 is a DNA-binding transcription factor acting at Pol II promoters as activator or repressor. Reason: Correct but general; the rat data show Pol II-specific activator activity (LAMC1, p53 promoters) and orthologous data show repressor activity (SMC markers, RARA). Replace with the specific Pol II activator/repressor terms. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | MODIFY | Summary: KLF4 is a DNA-binding transcription factor acting at Pol II promoters as activator or repressor. Reason: Correct but general; the rat data show Pol II-specific activator activity (LAMC1, p53 promoters) and orthologous data show repressor activity (SMC markers, RARA). Replace with the specific Pol II activator/repressor terms. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 is a DNA-binding transcription factor acting at Pol II promoters as activator or repressor. Reason: Correct but general; the rat data show Pol II-specific activator activity (LAMC1, p53 promoters) and orthologous data show repressor activity (SMC markers, RARA). Replace with the specific Pol II activator/repressor terms. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term, so both Pol II activator and repressor terms are proposed Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 is a DNA-binding transcription factor acting at Pol II promoters as activator or repressor. Reason: Correct but general; the rat data show Pol II-specific activator activity (LAMC1, p53 promoters) and orthologous data show repressor activity (SMC markers, RARA). Replace with the specific Pol II activator/repressor terms. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O43474 Β· human KLF4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term, so both Pol II activator and repressor terms are proposed Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription repressor activity, RNA polymerase II-specific Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: KLF4 is a nuclear transcription factor. Reason: Consistent with its promoter binding in chromatin (rat ChIP); core location. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 is a nuclear transcription factor. Reason: Consistent with its promoter binding in chromatin (rat ChIP); core location. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter |
| GO:0005634 nucleus | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 is a nuclear transcription factor. Reason: Consistent with its promoter binding in chromatin (rat ChIP); core location. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter |
| GO:0005667 transcription regulator complex | IDA PMID:15632413 Combinatorial control of the bradykinin B2 receptor promoter... | KEEP AS NON CORE | Summary: KLF4 assembles with CREB, p53 and CBP on the B2R enhancer. Reason: Supported by rat ChIP data; transient promoter-bound assemblies rather than a stable complex membership. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 assembles with CREB, p53 and CBP on the B2R enhancer. Reason: Supported by rat ChIP data; transient promoter-bound assemblies rather than a stable complex membership. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation |
| GO:0005667 transcription regulator complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 assembles with CREB, p53 and CBP on the B2R enhancer. Reason: Supported by rat ChIP data; transient promoter-bound assemblies rather than a stable complex membership. Supporting Evidence: PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cytoplasmic localization transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. KLF4 acts in the nucleus; cytoplasmic pools are reported in some cell types but are peripheral. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Cytoplasmic localization transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. KLF4 acts in the nucleus; cytoplasmic pools are reported in some cell types but are peripheral. |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 is a sequence-specific regulator of transcription, not a component of the transcription machinery. Reason: A DNA-binding transcription factor regulates rather than executes DNA-templated transcription; replace with the regulation terms it carries. Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0006351 DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 is a sequence-specific regulator of transcription, not a component of the transcription machinery. Reason: A DNA-binding transcription factor regulates rather than executes DNA-templated transcription; replace with the regulation terms it carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS SOURCE BUT NOT TARGET source annotation not inspected here; a DNA-binding transcription factor regulates rather than executes transcription, so the term carries the wrong role Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0006357 regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 both activates and represses Pol II transcription. Reason: Correct but general; both specific directions are supported, so both descendants are listed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term, so both positive and negative Pol II regulation terms are proposed Proposed replacements: positive regulation of transcription by RNA polymerase II negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0008013 beta-catenin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Beta-catenin binding transferred from human/mouse KLF4, where KLF4 binds beta-catenin and antagonizes TCF-dependent transcription. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Plausible peripheral interaction; not demonstrated in rat. |
| GO:0008013 beta-catenin binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Beta-catenin binding transferred from human/mouse KLF4, where KLF4 binds beta-catenin and antagonizes TCF-dependent transcription. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Plausible peripheral interaction; not demonstrated in rat. |
| GO:0008285 negative regulation of cell population proliferation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 is a growth-inhibitory factor in several cell types (VSMCs, epithelia), acting via p21 induction. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Holds across cell types; the more specific SMC term is accepted separately. Supporting Evidence: PMID:18483411 cultured SMCs overexpressing Klf4 showed reduced cellular proliferation, in part, through the induction of the cell cycle inhibitor, p21(WAF1/Cip1) PMID:17659301 Overexpression of GKLF significantly reduced VSMC proliferation |
| GO:0008544 epidermis development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse Klf4 knockout disrupts late-stage epidermal development. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Developmental role inferred from mouse knockout. Supporting Evidence: PMID:10431239 Klf4-/- mice die shortly after birth due to loss of skin barrier function |
| GO:0008544 epidermis development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Mouse Klf4 knockout disrupts late-stage epidermal development. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Developmental role inferred from mouse knockout. Supporting Evidence: PMID:10431239 Klf4-/- mice die shortly after birth due to loss of skin barrier function |
| GO:0009913 epidermal cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 is required for late epidermal differentiation in mouse. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Developmental role inferred from mouse knockout. Supporting Evidence: PMID:10431239 highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition |
| GO:0010467 gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic 'gene expression' transferred from ortholog phenotype data. Reason: KLF4 regulates transcription of target genes, captured by the Pol II regulation terms; 'gene expression' as a process KLF4 is involved in is uninformative and not what the product does. |
| GO:0010467 gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Generic 'gene expression' transferred from ortholog phenotype data. Reason: KLF4 regulates transcription of target genes, captured by the Pol II regulation terms; 'gene expression' as a process KLF4 is involved in is uninformative and not what the product does. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SOURCE WEAK OR INFERRED row summary describes the source as ortholog phenotype data (source annotation not re-inspected here); generic gene expression is uninformative beside the Pol II regulation terms |
| GO:0010467 gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Generic 'gene expression' transferred from ortholog phenotype data. Reason: KLF4 regulates transcription of target genes, captured by the Pol II regulation terms; 'gene expression' as a process KLF4 is involved in is uninformative and not what the product does. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SOURCE WEAK OR INFERRED row summary describes the source as ortholog phenotype data (source annotation not re-inspected here); generic gene expression is uninformative beside the Pol II regulation terms |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 increases target gene expression by activating transcription. Reason: Correct but general; the mechanism is transcriptional activation (GO:0045944, already carried). Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression |
| GO:0010628 positive regulation of gene expression | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 increases target gene expression by activating transcription. Reason: Correct but general; the mechanism is transcriptional activation (GO:0045944, already carried). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O43474 Β· human KLF4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 decreases target gene expression by repressing transcription. Reason: Correct but general; the mechanism is transcriptional repression (GO:0000122, already carried). Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 decreases target gene expression by repressing transcription. Reason: Correct but general; the mechanism is transcriptional repression (GO:0000122, already carried). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O43474 Β· human KLF4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes |
| GO:0014740 negative regulation of muscle hyperplasia | IMP PMID:19531492 KrΓΌppel-like factor 4 inhibits proliferation by platelet-der... | KEEP AS NON CORE | Summary: KLF4 limits neointimal formation (SMC hyperplasia) after vascular injury. Reason: Supported by the cited study, but a tissue-level outcome of the antiproliferative role captured by GO:0048662. Supporting Evidence: PMID:19531492 The anti-proliferative effects of Klf4 on neointimal formation depend largely on PDGFR-mediated PI3K signaling |
| GO:0016525 negative regulation of angiogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of angiogenesis transferred from endothelial KLF4 studies. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Endothelial roles of KLF4 are context-dependent (it also carries positive regulation of sprouting angiogenesis); peripheral. |
| GO:0016525 negative regulation of angiogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of angiogenesis transferred from endothelial KLF4 studies. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Endothelial roles of KLF4 are context-dependent (it also carries positive regulation of sprouting angiogenesis); peripheral. |
| GO:0019827 stem cell population maintenance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 contributes to pluripotency networks (one of the reprogramming factors) in mouse ES cells. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-specific role (pluripotent cells), peripheral to the rat somatic-tissue literature. Supporting Evidence: PMID:16904174 introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions |
| GO:0019827 stem cell population maintenance | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 contributes to pluripotency networks (one of the reprogramming factors) in mouse ES cells. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-specific role (pluripotent cells), peripheral to the rat somatic-tissue literature. Supporting Evidence: PMID:16904174 introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions |
| GO:0019827 stem cell population maintenance | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 contributes to pluripotency networks (one of the reprogramming factors) in mouse ES cells. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-specific role (pluripotent cells), peripheral to the rat somatic-tissue literature. Supporting Evidence: PMID:16904174 introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions |
| GO:0030154 cell differentiation | ISO GO_REF:0000121 | MODIFY | Summary: Generic cell differentiation from ortholog phenotype data. Reason: Correct but general; the supported specific differentiation processes (epidermal, adipocyte) are already carried and are listed as replacements. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term; row summary describes the source as ortholog phenotype data Proposed replacements: epidermal cell differentiation fat cell differentiation Supporting Evidence: PMID:10431239 highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition |
| GO:0030336 negative regulation of cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of cell migration transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral cellular outcome. |
| GO:0030336 negative regulation of cell migration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of cell migration transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral cellular outcome. |
| GO:0031077 post-embryonic camera-type eye development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Post-embryonic eye development role transferred from mouse conditional knockout data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Phenotype-based, peripheral. |
| GO:0031490 chromatin DNA binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 occupies promoter DNA in chromatin (ChIP), consistent with chromatin DNA binding. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with rat and mouse ChIP data; a context description of its DNA binding rather than a distinct activity. Supporting Evidence: PMID:12970361 results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation |
| GO:0031490 chromatin DNA binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 occupies promoter DNA in chromatin (ChIP), consistent with chromatin DNA binding. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with rat and mouse ChIP data; a context description of its DNA binding rather than a distinct activity. Supporting Evidence: PMID:12970361 results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin PMID:15632413 assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation |
| GO:0032206 positive regulation of telomere maintenance | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of telomere maintenance (via TERT transcription) transferred from human data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Downstream consequence of transcriptional activation; peripheral. |
| GO:0032526 response to retinoic acid | ISO GO_REF:0000121 | MODIFY | Summary: Response to retinoic acid. Reason: Correct but general; the rat data concern the cellular response (GO:0071300), already carried. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: cellular response to retinoic acid Supporting Evidence: PMID:21252119 ATRA and PDGF-BB induced KLF4 expression |
| GO:0032717 negative regulation of interleukin-8 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 limits pro-inflammatory chemokine production (IL-8) in endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Part of the anti-inflammatory endothelial programme; peripheral. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:0032717 negative regulation of interleukin-8 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 limits pro-inflammatory chemokine production (IL-8) in endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Part of the anti-inflammatory endothelial programme; peripheral. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:0034115 negative regulation of heterotypic cell-cell adhesion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 reduces leukocyte adhesion to endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Supported by human/mouse endothelial data; peripheral. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:0034115 negative regulation of heterotypic cell-cell adhesion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 reduces leukocyte adhesion to endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Supported by human/mouse endothelial data; peripheral. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:0035014 phosphatidylinositol 3-kinase regulator activity | IMP PMID:19531492 KrΓΌppel-like factor 4 inhibits proliferation by platelet-der... | MARK AS OVER ANNOTATED | Summary: The study shows that KLF4 inhibits PI3K and ERK signalling in VSMCs by binding the RARA regulatory region and repressing RARA and PDGFRB expression. Reason: The molecular-function term asserts that KLF4 itself modulates PI3K activity. The abstract attributes the effect to transcriptional repression of the receptors upstream of PI3K, i.e. an indirect consequence of KLF4's transcription factor activity; there is no evidence that KLF4 binds or regulates the kinase. The process-level consequence is retained via GO:0051898. Full text not cached, so the experimental row is marked over-annotated rather than removed; flagged for expert confirmation. Supporting Evidence: PMID:19531492 Klf4 inhibits RAR alpha and PDGFR beta expression while blocking PI3K and ERK signaling induced by Am80 and PDGF-BB, respectively PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression file:rat/Klf4/Klf4-deep-research-manual.md The effect on PI3K is therefore transcriptional and indirect. |
| GO:0035166 post-embryonic hemopoiesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Post-embryonic hemopoiesis role (monocyte differentiation) transferred from mouse data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Phenotype-based, peripheral. |
| GO:0035166 post-embryonic hemopoiesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Post-embryonic hemopoiesis role (monocyte differentiation) transferred from mouse data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Phenotype-based, peripheral. |
| GO:0042127 regulation of cell population proliferation | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 regulates cell proliferation, consistently in the inhibitory direction. Reason: Correct but general; the direction is negative (GO:0008285, already carried). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: negative regulation of cell population proliferation Supporting Evidence: PMID:17659301 Overexpression of GKLF significantly reduced VSMC proliferation |
| GO:0042826 histone deacetylase binding | IPI PMID:19486889 All-trans retinoic acid increases KLF4 acetylation by induci... | KEEP AS NON CORE | Summary: HDAC2 binds and deacetylates KLF4 in rat VSMCs; ATRA dissociates the complex. Reason: Interaction is supported (IPI). KLF4 is the substrate here, so the binding is a regulatory input rather than a core activity. Supporting Evidence: PMID:19486889 inhibited the interaction of HDAC2 with KLF4 PMID:19486889 HDAC2 directly deacetylated KLF4 |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 dampens NF-kappaB-dependent inflammatory signalling in endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory role. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 dampens NF-kappaB-dependent inflammatory signalling in endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory role. |
| GO:0043565 sequence-specific DNA binding | IDA PMID:12034813 Synergistic activation of the rat laminin gamma1 chain promo... | MODIFY | Summary: KLF4 binds specific GC/CACCC elements of promoters (bcn-1 of LAMC1, B2R enhancer, p53 promoter). Reason: Correct but general; replace with the specific Pol II cis-regulatory sequence-specific DNA binding term already carried by the gene. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12034813 We show that GKLF binds bcn-1, but this binding is not required for the GKLF-mediated activation of the LAMC1 promoter. PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0043565 sequence-specific DNA binding | IDA PMID:15632413 Combinatorial control of the bradykinin B2 receptor promoter... | MODIFY | Summary: KLF4 binds specific GC/CACCC elements of promoters (bcn-1 of LAMC1, B2R enhancer, p53 promoter). Reason: Correct but general; replace with the specific Pol II cis-regulatory sequence-specific DNA binding term already carried by the gene. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12034813 We show that GKLF binds bcn-1, but this binding is not required for the GKLF-mediated activation of the LAMC1 promoter. PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0043565 sequence-specific DNA binding | IDA PMID:17659301 Induction of p53 by GKLF is essential for inhibition of prol... | MODIFY | Summary: KLF4 binds specific GC/CACCC elements of promoters (bcn-1 of LAMC1, B2R enhancer, p53 promoter). Reason: Correct but general; replace with the specific Pol II cis-regulatory sequence-specific DNA binding term already carried by the gene. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12034813 We show that GKLF binds bcn-1, but this binding is not required for the GKLF-mediated activation of the LAMC1 promoter. PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 binds specific GC/CACCC elements of promoters (bcn-1 of LAMC1, B2R enhancer, p53 promoter). Reason: Correct but general; replace with the specific Pol II cis-regulatory sequence-specific DNA binding term already carried by the gene. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12034813 We show that GKLF binds bcn-1, but this binding is not required for the GKLF-mediated activation of the LAMC1 promoter. PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0043565 sequence-specific DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 binds specific GC/CACCC elements of promoters (bcn-1 of LAMC1, B2R enhancer, p53 promoter). Reason: Correct but general; replace with the specific Pol II cis-regulatory sequence-specific DNA binding term already carried by the gene. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12034813 We show that GKLF binds bcn-1, but this binding is not required for the GKLF-mediated activation of the LAMC1 promoter. PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 induces endothelial nitric-oxide synthase expression. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Transcriptional induction of NOS3; peripheral to the core activity. Supporting Evidence: PMID:17339326 Overexpression of Kruppel-like factor 4 induces expression of multiple anti-inflammatory and anti-thrombotic factors including endothelial nitric-oxide synthase and thrombomodulin |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 induces endothelial nitric-oxide synthase expression. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Transcriptional induction of NOS3; peripheral to the core activity. Supporting Evidence: PMID:17339326 Overexpression of Kruppel-like factor 4 induces expression of multiple anti-inflammatory and anti-thrombotic factors including endothelial nitric-oxide synthase and thrombomodulin |
| GO:0045444 fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Fat cell differentiation role transferred from mouse data (KLF4 as an early adipogenic regulator). Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral, cell-type-specific role. |
| GO:0045444 fat cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Fat cell differentiation role transferred from mouse data (KLF4 as an early adipogenic regulator). Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral, cell-type-specific role. |
| GO:0045444 fat cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Fat cell differentiation role transferred from mouse data (KLF4 as an early adipogenic regulator). Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral, cell-type-specific role. |
| GO:0045595 regulation of cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 modulates differentiation of several cell types (SMC marker genes, epidermis, adipocytes). Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Direction is cell-type dependent (it represses SMC markers in mouse but supports SM22alpha activation by ATRA in rat), so the general regulation term is as precise as warranted. Supporting Evidence: PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes PMID:19486889 KLF4 acetylation and binding activity of KLF4 to the SM22alpha promoter were significantly increased in ATRA-treated VSMCs |
| GO:0045595 regulation of cell differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 modulates differentiation of several cell types (SMC marker genes, epidermis, adipocytes). Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Direction is cell-type dependent (it represses SMC markers in mouse but supports SM22alpha activation by ATRA in rat), so the general regulation term is as precise as warranted. Supporting Evidence: PMID:12970361 a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes PMID:19486889 KLF4 acetylation and binding activity of KLF4 to the SM22alpha promoter were significantly increased in ATRA-treated VSMCs |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | MODIFY | Summary: KLF4-mediated repression (e.g. of RARA) is transcription by RNA polymerase II. Reason: Correct but general; the specific Pol II term GO:0000122, already carried, is supported. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0045892 negative regulation of DNA-templated transcription | IMP PMID:19531492 KrΓΌppel-like factor 4 inhibits proliferation by platelet-der... | MODIFY | Summary: KLF4-mediated repression (e.g. of RARA) is transcription by RNA polymerase II. Reason: Correct but general; the specific Pol II term GO:0000122, already carried, is supported. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0045892 negative regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: KLF4-mediated repression (e.g. of RARA) is transcription by RNA polymerase II. Reason: Correct but general; the specific Pol II term GO:0000122, already carried, is supported. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0045892 negative regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: KLF4-mediated repression (e.g. of RARA) is transcription by RNA polymerase II. Reason: Correct but general; the specific Pol II term GO:0000122, already carried, is supported. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O43474 Β· human KLF4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0045892 negative regulation of DNA-templated transcription | ISS GO_REF:0000024 | MODIFY | Summary: KLF4-mediated repression (e.g. of RARA) is transcription by RNA polymerase II. Reason: Correct but general; the specific Pol II term GO:0000122, already carried, is supported. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:19531492 Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000120 | MODIFY | Summary: KLF4-mediated activation acts on Pol II promoters. Reason: Correct but general; replace with GO:0045944, already carried. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression |
| GO:0045893 positive regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: KLF4-mediated activation acts on Pol II promoters. Reason: Correct but general; replace with GO:0045944, already carried. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression |
| GO:0045893 positive regulation of DNA-templated transcription | ISO GO_REF:0000121 | MODIFY | Summary: KLF4-mediated activation acts on Pol II promoters. Reason: Correct but general; replace with GO:0045944, already carried. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O43474 Β· human KLF4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12034813 Synergistic activation of the rat laminin gamma1 chain promo... | ACCEPT | Summary: KLF4 directly activates Pol II promoters (LAMC1, p53, p21, B2R). Reason: Core process, supported by rat reporter experiments and conserved across mammals. Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:17659301 Induction of p53 by GKLF is essential for inhibition of prol... | ACCEPT | Summary: KLF4 directly activates Pol II promoters (LAMC1, p53, p21, B2R). Reason: Core process, supported by rat reporter experiments and conserved across mammals. Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: KLF4 directly activates Pol II promoters (LAMC1, p53, p21, B2R). Reason: Core process, supported by rat reporter experiments and conserved across mammals. Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 directly activates Pol II promoters (LAMC1, p53, p21, B2R). Reason: Core process, supported by rat reporter experiments and conserved across mammals. Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 directly activates Pol II promoters (LAMC1, p53, p21, B2R). Reason: Core process, supported by rat reporter experiments and conserved across mammals. Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000121 | ACCEPT | Summary: KLF4 directly activates Pol II promoters (LAMC1, p53, p21, B2R). Reason: Core process, supported by rat reporter experiments and conserved across mammals. Supporting Evidence: PMID:12034813 the synergistic action of GKLF and Sp1 is dependent on the promoter context and the integrity of GKLF activation and DNA-binding domain PMID:17659301 GKLF overexpression led to an enhanced p53 promoter activity and increased p53 mRNA and protein expression PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter |
| GO:0046985 positive regulation of hemoglobin biosynthetic process | IEA GO_REF:0000107 | UNDECIDED | Summary: Positive regulation of hemoglobin biosynthetic process transferred from ortholog data. Reason: I could not access the ortholog source experiment; KLF1 rather than KLF4 is the canonical globin regulator, and no supporting evidence for KLF4 was found in the cached literature. |
| GO:0046985 positive regulation of hemoglobin biosynthetic process | ISO GO_REF:0000121 | UNDECIDED | Summary: Positive regulation of hemoglobin biosynthetic process transferred from ortholog data. Reason: I could not access the ortholog source experiment; KLF1 rather than KLF4 is the canonical globin regulator, and no supporting evidence for KLF4 was found in the cached literature. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:O43474 Β· human KLF4 UNRESOLVED source experiment could not be accessed; KLF1 rather than KLF4 is the canonical globin regulator, and no KLF4 support was found in cached literature |
| GO:0048662 negative regulation of smooth muscle cell proliferation | IDA PMID:17659301 Induction of p53 by GKLF is essential for inhibition of prol... | ACCEPT | Summary: In rat aortic VSMCs KLF4 inhibits proliferation via induction of p53/p21 and repression of PDGFRB-PI3K signalling; mouse knockout increases medial SMC proliferation after injury. Reason: Best-supported biological role of rat Klf4 (overexpression, antisense and in vivo neointima data in rat; conditional KO in mouse). Supporting Evidence: PMID:17659301 Overexpression of GKLF significantly reduced VSMC proliferation PMID:19531492 The anti-proliferative effects of Klf4 on neointimal formation depend largely on PDGFR-mediated PI3K signaling PMID:18483411 Klf4 mutant mice exhibited enhanced neointimal formation in response to vascular injury caused by increased cellular proliferation in the media |
| GO:0048662 negative regulation of smooth muscle cell proliferation | IMP PMID:19531492 KrΓΌppel-like factor 4 inhibits proliferation by platelet-der... | ACCEPT | Summary: In rat aortic VSMCs KLF4 inhibits proliferation via induction of p53/p21 and repression of PDGFRB-PI3K signalling; mouse knockout increases medial SMC proliferation after injury. Reason: Best-supported biological role of rat Klf4 (overexpression, antisense and in vivo neointima data in rat; conditional KO in mouse). Supporting Evidence: PMID:17659301 Overexpression of GKLF significantly reduced VSMC proliferation PMID:19531492 The anti-proliferative effects of Klf4 on neointimal formation depend largely on PDGFR-mediated PI3K signaling PMID:18483411 Klf4 mutant mice exhibited enhanced neointimal formation in response to vascular injury caused by increased cellular proliferation in the media |
| GO:0048679 regulation of axon regeneration | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of axon regeneration transferred from mouse retinal ganglion cell data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Phenotype-based, peripheral. |
| GO:0048730 epidermis morphogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Epidermis morphogenesis role transferred from mouse knockout data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Phenotype-based developmental annotation; peripheral. |
| GO:0051247 positive regulation of protein metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of protein metabolic process transferred from ortholog data. Reason: Very broad indirect consequence of increased target-gene transcription; uninformative about KLF4 function. |
| GO:0051247 positive regulation of protein metabolic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Positive regulation of protein metabolic process transferred from ortholog data. Reason: Very broad indirect consequence of increased target-gene transcription; uninformative about KLF4 function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O43474 Β· human KLF4 UNRESOLVED source annotation not inspected here; the term is a very broad indirect consequence of increased target-gene transcription |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:19531492 KrΓΌppel-like factor 4 inhibits proliferation by platelet-der... | KEEP AS NON CORE | Summary: KLF4 dampens PI3K/AKT signalling in VSMCs by repressing RARA and PDGFRB expression. Reason: Supported by IMP, but indirect (transcriptional control of receptor levels); peripheral to the core TF activity. Supporting Evidence: PMID:19531492 Klf4 inhibits RAR alpha and PDGFR beta expression while blocking PI3K and ERK signaling induced by Am80 and PDGF-BB, respectively |
| GO:0060070 canonical Wnt signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 binds beta-catenin and antagonizes canonical Wnt target gene activation in ortholog studies. Reason: KLF4 is an inhibitor of canonical Wnt/beta-catenin signalling, not a participant in the pathway; the annotation should carry the negative-regulation term. Proposed replacements: negative regulation of canonical Wnt signaling pathway |
| GO:0060070 canonical Wnt signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 binds beta-catenin and antagonizes canonical Wnt target gene activation in ortholog studies. Reason: KLF4 is an inhibitor of canonical Wnt/beta-catenin signalling, not a participant in the pathway; the annotation should carry the negative-regulation term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1342287 Β· mouse Klf4 SUPPORTS SOURCE BUT NOT TARGET source annotation not inspected here; ortholog studies show KLF4 antagonizes canonical Wnt target activation, so it is a negative regulator, not a pathway participant Proposed replacements: negative regulation of canonical Wnt signaling pathway |
| GO:0060761 negative regulation of response to cytokine stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 dampens endothelial responses to TNF-alpha and other cytokines. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory role. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:0060761 negative regulation of response to cytokine stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 dampens endothelial responses to TNF-alpha and other cytokines. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory role. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:0061436 establishment of skin barrier | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Klf4 is required for skin barrier acquisition in mouse. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Strong mouse knockout evidence; developmental, not core molecular function. Supporting Evidence: PMID:10431239 Klf4-/- mice die shortly after birth due to loss of skin barrier function PMID:10431239 highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition |
| GO:0061436 establishment of skin barrier | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Klf4 is required for skin barrier acquisition in mouse. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Strong mouse knockout evidence; developmental, not core molecular function. Supporting Evidence: PMID:10431239 Klf4-/- mice die shortly after birth due to loss of skin barrier function PMID:10431239 highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: KLF4 physically interacts with other Pol II DNA-binding transcription factors such as p53 and Sp1. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Supported by the p53-GKLF interaction in mammalian cells; cooperative factor binding is peripheral to the core activity. Supporting Evidence: PMID:10749849 a physical interaction between p53 and GKLF |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 physically interacts with other Pol II DNA-binding transcription factors such as p53 and Sp1. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Supported by the p53-GKLF interaction in mammalian cells; cooperative factor binding is peripheral to the core activity. Supporting Evidence: PMID:10749849 a physical interaction between p53 and GKLF |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 physically interacts with other Pol II DNA-binding transcription factors such as p53 and Sp1. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Supported by the p53-GKLF interaction in mammalian cells; cooperative factor binding is peripheral to the core activity. Supporting Evidence: PMID:10749849 a physical interaction between p53 and GKLF |
| GO:0070301 cellular response to hydrogen peroxide | IEP PMID:18406357 Differential regulation of KrΓΌppel-like factor family transc... | KEEP AS NON CORE | Summary: H2O2 induces Klf4 mRNA in neonatal rat cardiac myocytes (ERK1/2-dependent). Reason: IEP evidence of expression induction; conventional support for a 'response to' term but peripheral to function. Supporting Evidence: PMID:18406357 H2O2 increased expression of Klf2, Klf4 and Klf6 |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IMP PMID:19531492 KrΓΌppel-like factor 4 inhibits proliferation by platelet-der... | KEEP AS NON CORE | Summary: KLF4 dampens PDGF-BB and Am80-induced ERK signalling in VSMCs by repressing receptor expression. Reason: Supported by IMP but indirect, via transcriptional repression of PDGFRB/RARA. Supporting Evidence: PMID:19531492 Klf4 inhibits RAR alpha and PDGFR beta expression while blocking PI3K and ERK signaling induced by Am80 and PDGF-BB, respectively |
| GO:0071300 cellular response to retinoic acid | IEP PMID:19486889 All-trans retinoic acid increases KLF4 acetylation by induci... | KEEP AS NON CORE | Summary: All-trans retinoic acid induces KLF4 expression and acetylation in rat VSMCs. Reason: Supported by rat VSMC data; a regulatory input to KLF4 rather than its function. Supporting Evidence: PMID:19486889 KLF4 acetylation and binding activity of KLF4 to the SM22alpha promoter were significantly increased in ATRA-treated VSMCs PMID:21252119 ATRA and PDGF-BB induced KLF4 expression |
| GO:0071363 cellular response to growth factor stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 is induced by growth factors such as PDGF-BB in VSMCs. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with rat VSMC data; an input to KLF4 rather than its function. Supporting Evidence: PMID:21252119 ATRA and PDGF-BB induced KLF4 expression |
| GO:0071363 cellular response to growth factor stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 is induced by growth factors such as PDGF-BB in VSMCs. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with rat VSMC data; an input to KLF4 rather than its function. Supporting Evidence: PMID:21252119 ATRA and PDGF-BB induced KLF4 expression |
| GO:0071499 cellular response to laminar fluid shear stress | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Endothelial KLF4 is induced by laminar shear stress. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Expression response; peripheral. Supporting Evidence: PMID:17339326 endothelial Kruppel-like factor 4 is induced by pro-inflammatory stimuli and shear stress |
| GO:0071499 cellular response to laminar fluid shear stress | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Endothelial KLF4 is induced by laminar shear stress. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Expression response; peripheral. Supporting Evidence: PMID:17339326 endothelial Kruppel-like factor 4 is induced by pro-inflammatory stimuli and shear stress |
| GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of endothelial migration in sprouting angiogenesis transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-dependent endothelial role; peripheral. |
| GO:0090051 negative regulation of cell migration involved in sprouting angiogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of endothelial migration in sprouting angiogenesis transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-dependent endothelial role; peripheral. |
| GO:0106222 lncRNA binding | IEA GO_REF:0000107 | UNDECIDED | Summary: lncRNA binding transferred from human/mouse KLF4. Reason: I could not access the source experiment for the ortholog annotation and no rat or mechanistic evidence for direct lncRNA binding by the zinc-finger domain was found; left undecided rather than accepted. |
| GO:0106222 lncRNA binding | ISO GO_REF:0000121 | UNDECIDED | Summary: lncRNA binding transferred from human/mouse KLF4. Reason: I could not access the source experiment for the ortholog annotation and no rat or mechanistic evidence for direct lncRNA binding by the zinc-finger domain was found; left undecided rather than accepted. Propagation Review Root cause: UNRESOLVED Sources checked: MGI:MGI:1342287 Β· mouse Klf4 UNRESOLVED source experiment could not be accessed; no rat or mechanistic evidence for direct lncRNA binding by the zinc-finger domain was found |
| GO:0120222 regulation of blastocyst development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Regulation of blastocyst development transferred from mouse data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Pluripotency-context role, peripheral. |
| GO:1902895 positive regulation of miRNA transcription | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of miRNA gene transcription transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with KLF4's activator function at Pol II promoters; a specific target class rather than a distinct role. |
| GO:1902895 positive regulation of miRNA transcription | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of miRNA gene transcription transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with KLF4's activator function at Pol II promoters; a specific target class rather than a distinct role. |
| GO:1903672 positive regulation of sprouting angiogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of sprouting angiogenesis transferred from endothelial KLF4 studies. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-dependent endothelial role; peripheral. |
| GO:1903672 positive regulation of sprouting angiogenesis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Positive regulation of sprouting angiogenesis transferred from endothelial KLF4 studies. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-dependent endothelial role; peripheral. |
| GO:1904998 negative regulation of leukocyte adhesion to arterial endothelial cell | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 reduces leukocyte adhesion to arterial endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory endothelial role. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:1904998 negative regulation of leukocyte adhesion to arterial endothelial cell | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 reduces leukocyte adhesion to arterial endothelium. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory endothelial role. Supporting Evidence: PMID:17339326 Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface |
| GO:1990830 cellular response to leukemia inhibitory factor | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 expression responds to LIF/STAT3 signalling in mouse ES cells. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Expression-response annotation; peripheral. |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: KLF4 binds double-stranded GC/CACCC elements in promoters. Reason: Correct but general; the specific descendant GO:0000978 (Pol II cis-regulatory region) is supported and already carried. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:1990837 sequence-specific double-stranded DNA binding | ISO GO_REF:0000121 | MODIFY | Summary: KLF4 binds double-stranded GC/CACCC elements in promoters. Reason: Correct but general; the specific descendant GO:0000978 (Pol II cis-regulatory region) is supported and already carried. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O43474 Β· human KLF4 SUPPORTS TRANSFER source annotation not inspected here; the transferred term is judged true for rat Klf4 but broader than the supported specific term Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:21252119 KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22Ξ± promoter PMID:18406357 Klfs bind to consensus GC-rich or CACCC sequences through the three C-terminal zinc fingers |
| GO:1990841 promoter-specific chromatin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 binds promoter regions within chromatin (ChIP at SMC marker and p21 promoters). Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with ChIP data; non-core restatement of the promoter DNA-binding activity. Supporting Evidence: PMID:12970361 results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin |
| GO:1990841 promoter-specific chromatin binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 binds promoter regions within chromatin (ChIP at SMC marker and p21 promoters). Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Consistent with ChIP data; non-core restatement of the promoter DNA-binding activity. Supporting Evidence: PMID:12970361 results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin |
| GO:1990859 cellular response to endothelin | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Endothelin-1 induces Klf4 as an immediate-early gene in neonatal rat cardiac myocytes. Reason: Expression response (IEP; the IEA row reflects the same claim); kept as non-core. Supporting Evidence: PMID:18406357 Thus, Klf2, Klf4 and Klf6 are regulated as IEGs in response to ET-1 |
| GO:1990859 cellular response to endothelin | IEP PMID:18406357 Differential regulation of KrΓΌppel-like factor family transc... | KEEP AS NON CORE | Summary: Endothelin-1 induces Klf4 as an immediate-early gene in neonatal rat cardiac myocytes. Reason: Expression response (IEP; the IEA row reflects the same claim); kept as non-core. Supporting Evidence: PMID:18406357 Thus, Klf2, Klf4 and Klf6 are regulated as IEGs in response to ET-1 |
| GO:2000134 negative regulation of G1/S transition of mitotic cell cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 inhibits G1/S progression by inducing p21WAF1/Cip1. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Mechanistically consistent with p21 induction; downstream of the core TF activity. Supporting Evidence: PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter PMID:18483411 cultured SMCs overexpressing Klf4 showed reduced cellular proliferation, in part, through the induction of the cell cycle inhibitor, p21(WAF1/Cip1) |
| GO:2000134 negative regulation of G1/S transition of mitotic cell cycle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 inhibits G1/S progression by inducing p21WAF1/Cip1. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Mechanistically consistent with p21 induction; downstream of the core TF activity. Supporting Evidence: PMID:10749849 GKLF activates p21(WAF1/Cip1) through a specific Sp1-like cis-element in the p21(WAF1/Cip1) proximal promoter PMID:18483411 cultured SMCs overexpressing Klf4 showed reduced cellular proliferation, in part, through the induction of the cell cycle inhibitor, p21(WAF1/Cip1) |
| GO:2000342 negative regulation of chemokine (C-X-C motif) ligand 2 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: KLF4 limits CXCL2 production in an anti-inflammatory context. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory outcome. |
| GO:2000342 negative regulation of chemokine (C-X-C motif) ligand 2 production | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: KLF4 limits CXCL2 production in an anti-inflammatory context. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Peripheral anti-inflammatory outcome. |
| GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of extrinsic apoptotic signalling transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-dependent survival effect; peripheral. |
| GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Negative regulation of extrinsic apoptotic signalling transferred from ortholog data. Reason: Rat row transferred from human/mouse KLF4 (ISO from RGD, or Ensembl Compara IEA); rat Klf4 is a 1:1 ortholog with conserved zinc-finger DNA-binding domain. Context-dependent survival effect; peripheral. |
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Download this section (compressed HTML)Q: Does the PI3K-inhibitory effect of KLF4 in rat VSMCs reported in PMID:19531492 involve any direct interaction of KLF4 with PI3K subunits, or is it entirely explained by transcriptional repression of RARA and PDGFRB (which would make the GO:0035014 molecular-function annotation unwarranted)?
Q: How do the opposing roles of KLF4 on SM22alpha (activation after ATRA in rat VSMCs versus repression of SMC markers after PDGF-BB or injury in mouse) map onto specific cis-elements and acetylation states, and should regulation of smooth muscle cell differentiation be annotated with a direction?
Experiment: Co-immunoprecipitation and in vitro kinase assays with recombinant KLF4 and PI3K p85/p110 in rat VSMCs, compared with RARA/PDGFRB knockdown, to test whether KLF4 regulates PI3K directly or only through receptor expression.
Type: biochemical interaction assay
Experiment: Genome-wide ChIP-seq of KLF4 in rat aortic VSMCs under ATRA versus PDGF-BB treatment, with acetylation-site mutants, to define activated versus repressed direct targets.
Type: ChIP-seq
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