Human FOXC1 (Q12948) was genuinely imported from UniProt and QuickGO before curation. The 143 original contexts project to 141 stored annotations; both duplicate groups and all three singleton annotation extensions are retained with their original source objects. The reviewed record has a 553-amino-acid displayed sequence and no enumerated alternative natural products.
The one core function is selective cis-regulatory DNA binding coupled to positive RNA polymerase II transcription in the nucleus. Original human WT reporter and endogenous promoter evidence supports that synthesis. Direct transcriptional targets, partner-mediated effects, mouse developmental consequences and cancer-context perturbations are kept distinct. The source guide and evidence map document selected original reading, abstract-only evidence, construct/species limits and unresolved assays.
The applied decisions are 37 ACCEPT, 47 KEEP_AS_NON_CORE, 38 TOO_GENERAL, 4 MODIFY and 15 UNDECIDED. Four supported binding refinements use filamin binding or RNA polymerase II-specific DNA-binding transcription-factor binding. Supported generic associations remain non-core where a functional subtype is not established. Inaccessible experimental detail is not treated as refutation. No NEW annotations, publication quotations or invented natural products were added.
All 40 normal dependencies are preserved byte-for-byte after genuine acquisition or exact-main hydration: 37 publications and three PANTHER files. The seven auxiliary donor papers support existing transfer contexts. Source flags are not full-paper reading claims. Six IBA origins were independently replayed; two donor/date snapshot differences remain explicitly recorded without source repair.
The candidate was applied after independent scientific review of the molecular-function, biological-process, cellular-component and binding proposals. Validation results will be appended after execution.
Default schema, reference-title, best-practice and ontology-term validation passed with 14 advisories. Strict GOA comparison passed, and the repository status computation resolves this candidate to DRAFT. The advisories are three intentionally retained generic-binding contexts, five term-level action differences caused by explicit source-specific uncertainty, and six accepted contexts without a supported_by entry. The exact source citations and rationale remain in those rows; no publication quotations were added to suppress a warning. The environment also emits a pkg_resources deprecation notice.
Exact conservation checks passed for all 143 original objects, 141 reviewed annotations, three extension atoms, 45 reference entries and 40 unchanged normal sources. The genuine CLI-generated history validates, and the private HTML render completes. Initial unpublished extension predicates were corrected from objects to the schema's required strings; an independent source check removed the unsupported BT549 description and retained only the checkable MDA-MB-231, mouse 4T1 and human nuclear-immunohistochemistry evidence. Neither correction changed an annotation decision. The initial status command reported the existing INITIALIZED mismatch without rewriting it; the repository's computed DRAFT result was then applied and the status check passed.
A further check of the retained PMID:20406990 extracts did not verify the earlier BT549/S8 inference. The current three rationales and source assessment therefore use only the checkable human MDA-MB-231 overexpression, mouse 4T1 knockdown and human nuclear immunohistochemistry. The earlier reading note is preserved with an additive superseding correction; all annotation actions and the core function remain unchanged.
Six accepted source contexts now explicitly link their already-read original paper through reference-only supported_by entries: stored rows 56, 62, 68, 69, 117 and 119. No quotation, annotation action, rationale, core function or source field changed. Final default validation passed with eight remaining advisories: three retained generic-binding contexts and five source-specific same-term action differences. The earlier 14-advisory outcome above is retained as the preceding validation record. Conservation, final history and private rendering were checked again for the completed candidate.
Human WT reporter and endogenous promoter experiments support nuclear FOXC1 transcriptional activation, including regulation of FOXO1 in ocular cells (PMID:11179011(../../../publications/PMID_11179011.md), PMID:17993506(../../../publications/PMID_17993506.md)). The original domain-mapping study also demonstrates a transferable inhibitory region. Its residues 215–366 attenuate activation-domain-driven reporter output but did not reduce the tested constitutive SV40 baseline without an activation domain. This is positive evidence for modular attenuation; it does not by itself establish a separate full-length DNA-binding repressor mechanism (PMID:11782474(../../../publications/PMID_11782474.md), original Results/Figure 5E and Discussion linked in the source guide).
Interaction assays have distinct scopes. The NFIA-associated signal in the original nuclear-extract/probe screen supports refinement to RNA polymerase II-specific DNA-binding transcription-factor binding because NFIA's class is established. It does not inherit PBX1's separate co-immunoprecipitation or inhibitory result, and NFIA did not impair FOXC1 activity in the tested cells (PMID:15684392(../../../publications/PMID_15684392.md)). The GLI2 cancer experiments support increased DNA-binding activity in that setting; they do not replay the separate mouse core-promoter-binding donor assay (PMID:26565916(../../../publications/PMID_26565916.md), PMID:25808752(../../../publications/PMID_25808752.md)).
Developmental effects retain their tissue context. FOXC1 variants cause anterior segment dysgenesis and increased glaucoma susceptibility. Mouse corneal stromal experiments establish corneal avascularity and transparency, which is distinct from ocular lens transparency (PMID:11782474(../../../publications/PMID_11782474.md), PMID:22171010(../../../publications/PMID_22171010.md)). Three structured, unreported source queries now identify the two human lens transfers and the exact mouse donor assertion. No replacement is guessed. A niche cell can regulate another cell’s differentiation; non-cell-autonomy alone does not establish over-annotation. The unresolved issue is the exact differentiation endpoint in the inaccessible assays (PMID:24590069(../../../publications/PMID_24590069.md)).
The revised questions and experiments address biological mechanisms. Source-access follow-up remains in the evidence map and here: the original FOXC1 assay attributed to PMID:11237714; the P297S letter PMID:19793056; the PMID:14506133 bending experiment; the exact PMID:25609649 FOXC1–PBX1 pair; the mouse PMID:28223138 negative-transcription assay; the PMID:24590069 differentiation assays; any lens-specific support beyond PMID:22171010; and the precise core-promoter assay in PMID:25808752. Curated UniProt attributions are acknowledged without claiming that inaccessible experiments were independently read.
The decisions are now 37 ACCEPT, 46 KEEP_AS_NON_CORE, 38 TOO_GENERAL, 5 MODIFY and 15 UNDECIDED. Only the NFIA source row changed action. All 143 original contexts, 141 stored machine records, three extension atoms, one core, 45 reference identifiers/titles and 40 normal-source bytes are preserved. No new annotation, natural product or publication quotation was added. Follow-up validation results will be appended after execution.
Default schema, ontology-term, reference and best-practice validation passed with seven advisories: two retained generic-binding associations and five source-specific same-term action differences. Strict GOA, computed DRAFT status, exact conservation and private rendering also passed. All 143 raw contexts, 141 stored machine records, three original extension atoms, 45 reference identifiers/titles and 40 normal-source files remain preserved. The three source queries are NOT_REPORTED. No new quotation or annotation was added. The markdown PMID helper found no pathway file, so it performed no pathway-text validation; the environment also emitted the existing pkg_resources deprecation notice.
The human FOXC1–GLI2 experiments support a second regulatory core: FOXC1 binds GLI2 and increases GLI2 DNA binding and transcriptional output in the studied breast-cancer cells (PMID:26565916(../../../publications/PMID_26565916.md)). This mechanism complements FOXC1’s own regulatory DNA binding and activation; the proposed allosteric structural explanation remains unresolved. The PBX1a association is refined to its supported Pol-II transcription-factor partner class using the same original paper and immutable P40424-1 context (PMID:15684392(../../../publications/PMID_15684392.md)).
All 37 PMID relevance assessments were considered independently of access quality: 30 HIGH, six MEDIUM and one provisional LOW. Historical identity/expression and clinical association sources remain supporting context; direct functional characterizations remain highly relevant even when a particular assay is inaccessible. PMID:11237714 is LOW only for the inspected DSCAM content, while its original experimental attribution remains unresolved without a wrong-identifier claim. The three P297S and one bending context retain UNDECIDED, with the reason documented in the source guide.
The campaign policy retains the two supported generic associations when no evidence-backed refinement is established. Clearly empty enzyme, receptor and motor caveats were removed while preserving assay, species, product, signal-direction and source-access limits. The decisions are 38 ACCEPT, 44 KEEP_AS_NON_CORE, 38 TOO_GENERAL, six MODIFY and 15 UNDECIDED; two cores, all 143 raw contexts, 141 machine records, three extension atoms, 45 references and 40 normal sources are preserved. No publication quotations or NEW annotations are added.
Default schema, ontology-term, reference and best-practice validation passed with seven advisories: two retained generic-binding associations and five source-specific same-term action differences. Strict GOA, computed DRAFT status, exact conservation and private rendering also passed. All 143 raw contexts, 141 stored machine records, three original extension atoms, 45 reference identifiers/titles and 40 normal-source files remain preserved. The three source queries are NOT_REPORTED. Two mechanisms are represented: direct FOXC1 regulatory DNA binding and activation, and GLI2-binding regulation in the tested human cancer-cell setting. No new quotation or annotation was added. The markdown PMID helper found no pathway file, so it performed no pathway-text validation; the environment also emitted the existing pkg_resources deprecation notice.