ALX1 (CART1) is a paired-like homeodomain transcription factor that recognizes regulatory DNA and can activate or repress transcription depending on the promoter and cellular context. It acts in the nucleus and is enriched at developmental regulatory chromatin in human cranial neural crest cell models. ALX1 contributes to craniofacial mesenchymal and skeletal patterning; biallelic human variants cause frontonasal dysplasia, while mouse and zebrafish studies resolve additional lineage and developmental-stage requirements. In responsive human epithelial and ovarian cancer models, ALX1 promotes SNAI1 expression and epithelial-to-mesenchymal transition. Its sequence recognition and transcriptional activity are established, whereas native oligomeric stoichiometry and the physiological roles of many high-throughput interaction partners remain less well resolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:8756334 Human Cart-1: structural organization, chromosomal localizat... | ACCEPT | Summary: Human ALX1 represses a promoter through a defined AT-rich regulatory element. Reason: The original human Cart1 cDNA study measures repression of a rat prolactin promoter through footprint II. The promoter species does not change the identity of the human protein tested. The abstract does not identify the reporter host, so it is not inferred from the separate HeLa/GH3/10T1/2 expression survey. This positive repression result complements activation on other promoters (PMID:9753625). Supporting Evidence: PMID:8756334 Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: ALX1 associates with transcriptional regulatory chromatin. Reason: The TFClass assertion is independently supported by endogenous-tag ALX1 ChIP-seq in human H9-derived cranial neural crest cells in PMID:38262408. Occupancy of Coordinator-containing enhancers is direct chromatin evidence. The same paper crystallizes ALX4, not ALX1; that paralog structure is not substituted for ALX1 biochemistry. Propagation Review Root cause: NO FAILURE CORE Sources checked: tfclass:3.1.3 SUPPORTS TRANSFER Classified paired-like homeodomain transcription factor; target chromatin occupancy independently inspected in human cranial neural crest cells. Supporting Evidence: PMID:38262408 However, the strength of ChIP signal is reproducibly distinct between the tagged HD TFs, with strongest signal for ALX1. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited regulatory DNA-binding activity is directly supported in human ALX1. Reason: PAINT assigns the activity at PTN004692309. Human hCART1 sequence selection, recombinant DNA binding and sequence-dependent reporter activation corroborate this conserved function (PMID:9753625). Q15699 among the descendant evidence is legitimate target experimental grounding, not circularity. The original IBD/tree was not independently reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN004692309 SUPPORTS TRANSFER Retain the curator-placed ancestral regulatory DNA-binding assertion, corroborated by direct human ALX1 experiments; no target loss or node-placement failure demonstrated. Supporting Evidence: PMID:9753625 It is reported here that all sites obtained contain a palindrome consisting of two TAAT sequences separated by three or four base pairs. PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:9753625 Human CART1, a paired-class homeodomain protein, activates t... | ACCEPT | Summary: Human ALX1 binds selected sites that confer transcriptional reporter activity. Reason: The original study selected palindromic sites, measured recombinant hCART1 binding by EMSA and tested site-dependent reporter activation in HeLa cells. These assays connect recognition to regulatory DNA function; they do not establish that every selected oligonucleotide is an endogenous human enhancer. Supporting Evidence: PMID:9753625 It is reported here that all sites obtained contain a palindrome consisting of two TAAT sequences separated by three or four base pairs. PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000002 | ACCEPT | Summary: The homeobox mapping agrees with experimentally established Pol II transcription factor activity. Reason: IPR017970 maps the homeobox conserved site. Human hCART1 binds defined DNA sequences and changes promoter-driven reporter expression (PMIDs:9753625,8756334), supporting the target-level activity independently of the domain prediction. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR017970 SUPPORTS TRANSFER Homeobox conserved-site mapping is corroborated by human sequence-specific transcription assays. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. PMID:8756334 Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: ALX1 is a sequence-specific RNA polymerase II transcription factor. Reason: TFClass assignment agrees with recombinant human DNA recognition, HeLa transactivation and promoter-specific repression. Activation and repression are context-dependent outputs of the same transcription factor rather than incompatible gene identities. Propagation Review Root cause: NO FAILURE CORE Sources checked: tfclass:3.1.3 SUPPORTS TRANSFER The classification is supported by direct human hCART1 functional assays. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. PMID:8756334 Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited activator activity is directly demonstrated for human ALX1. Reason: The PTN002803087 assertion is grounded in the human descendant hCART1 reporter assays. A source list containing Q15699 is expected when target evidence helped the curator place the IBD; it is not evidence of circularity. Repression on a different promoter does not invalidate positive activation in HeLa. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002803087 SUPPORTS TRANSFER Direct human ALX1 site- and dose-dependent reporter activation supports the inherited activator function; exact IBD reconstruction was not recovered. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:9753625 Human CART1, a paired-class homeodomain protein, activates t... | ACCEPT | Summary: Human ALX1 activates transcription in a DNA-site-dependent assay. Reason: The original abstract explicitly identifies human hCART1 and HeLa reporter transfection, with both site and dosage dependence. Recombinant DNA binding supplies the mechanistic connection between ALX1 and reporter activation. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. PMID:9753625 It is reported here that all sites obtained contain a palindrome consisting of two TAAT sequences separated by three or four base pairs. |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | TAS PMID:8756334 Human Cart-1: structural organization, chromosomal localizat... | ACCEPT | Summary: Retain the true activator function while distinguishing the cited repression study. Reason: The accessible PMID:8756334 abstract foregrounds repression of rat prolactin and does not independently expose the basis of this TAS activator assertion. Its unrecovered full text is not evidence of a miscitation. Human activation is directly established by PMID:9753625, so the biological annotation is retained with that explicit corroboration and the original source identity unchanged. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: The homeodomain mapping correctly identifies ALX1 DNA binding. Reason: IPR001356 supports the broad DNA-binding property of the homeodomain, corroborated by human hCART1 site selection and recombinant binding in PMID:9753625. The separate GO:0000981 annotation and integrated core already capture the more specific Pol II transcription factor activity. A valid domain-level mapping need not be replaced merely because target-level evidence is more specific. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001356 SUPPORTS TRANSFER The homeodomain mapping is biologically correct for ALX1 and independently corroborated by human sequence-selective DNA binding. Supporting Evidence: PMID:9753625 It is reported here that all sites obtained contain a palindrome consisting of two TAAT sequences separated by three or four base pairs. PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000107 | MODIFY | Summary: Refine the conserved transcription factor activity to its demonstrated Pol II scope. Reason: The Compara donor is mouse Alx1 (Q8C8B0), a member of the same ALX1 subfamily as human Q15699. The broad activity is consistent with mouse developmental transcription and direct human promoter assays. Human target experiments justify GO:0000981 without requiring an unverified donor-specific assay claim. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8C8B0 SUPPORTS TRANSFER Mouse Alx1 donor identity and shared PTHR24329:SF359 membership are verified; direct human reporter activity resolves the target specificity. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. PMID:8756334 Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | UNDECIDED | Summary: The curated ALX1–IPO13 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–IPO13 (UniProtKB:O94829), also recorded in human ALX1 UniProt. PMID:16189514 is abstract-only locally and does not expose the ALX1–IPO13 experimental record. The unresolved issue is the evidence needed to assess the interaction and any more informative ALX1 function, not the truth of its curated identifier. The standing access rule therefore requires UNDECIDED; this pair alone does not establish ALX1 as a nuclear transport factor. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–CLIC3 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–CLIC3 (UniProtKB:O95833), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. Partner identity alone does not establish a specific catalytic, adapter or regulatory activity for ALX1. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–APCS interaction awaits target-level source resolution. Reason: The curated pair is ALX1–APCS (UniProtKB:P02743), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. Partner identity alone does not establish a specific catalytic, adapter or regulatory activity for ALX1. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–GRP interaction awaits target-level source resolution. Reason: The curated pair is ALX1–GRP (UniProtKB:P07492), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. Partner identity alone does not establish a specific catalytic, adapter or regulatory activity for ALX1. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–RARA interaction awaits target-level source resolution. Reason: The curated pair is ALX1–RARA (UniProtKB:P10276), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. RARA has a nuclear transcriptional role, making shared nuclear context plausible, but its own receptor activity does not establish an ALX1 cofactor mechanism. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–EEF1D isoform 2 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–EEF1D isoform 2 (UniProtKB:P29692-2), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. The source specifies EEF1D isoform 2; its isoform scope is retained, without generalizing to every product of the partner gene. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–RBM45 isoform 3 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–RBM45 isoform 3 (UniProtKB:Q8IUH3-3), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. The source specifies RBM45 isoform 3; its isoform scope is retained, without generalizing to every product of the partner gene. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–PACRGL isoform 2 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–PACRGL isoform 2 (UniProtKB:Q8N7B6-2), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. The source specifies PACRGL isoform 2; its isoform scope is retained, without generalizing to every product of the partner gene. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–OR52L1 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–OR52L1 (UniProtKB:Q8NGH7), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. OR52L1 is a multipass cell-membrane receptor, unlike the established nuclear ALX1 context; that mismatch motivates physiological and construct-level checks, not rejection of an uninspected experimental interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–KAT5 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–KAT5 (UniProtKB:Q92993), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. KAT5 is a chromatin-associated acetyltransferase, making shared nuclear context plausible, but neither its catalysis nor a coactivator-binding role is transferred to ALX1 from the pair. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–UROC1 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–UROC1 (UniProtKB:Q96N76), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. Partner identity alone does not establish a specific catalytic, adapter or regulatory activity for ALX1. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–ZNF300 isoform 3 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–ZNF300 isoform 3 (UniProtKB:Q96RE9-3), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. The source specifies ZNF300 isoform 3; its isoform scope is retained, without generalizing to every product of the partner gene. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The curated ALX1–KRTAP4-4 interaction awaits target-level source resolution. Reason: The curated pair is ALX1–KRTAP4-4 (UniProtKB:Q9BYR3), also recorded in human ALX1 UniProt. The cached HuRI body in PMID:32296183 describes screening and dataset-level validation but contains no ALX1/CART1/Q15699 pair record; Supplementary Table 9 and this pair's validation assignment remain uninspected. Thus a more informative ALX1 function cannot be adjudicated from the body alone, and the source-access rule requires UNDECIDED. The KRTAP4-4 identity is retained exactly; no shared nuclear compartment, transcriptional role or incorrect-assay conclusion is inferred from the partner name. |
| GO:0005634 nucleus | EXP PMID:8756334 Human Cart-1: structural organization, chromosomal localizat... | ACCEPT | Summary: Retain human ALX1 nuclear localization. Reason: The original PMID:8756334 localization experiment is not visible in its cached abstract, but curator annotation and UniProt attribution are corroborated by the explicit human nuclear localization in PMID:9753625. This supports acceptance without inventing the original imaging assay. Supporting Evidence: PMID:9753625 It is also shown here that hCART1 localizes to nucleus. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization is conserved and directly demonstrated in human ALX1. Reason: PTN004692309 nuclear inheritance agrees with explicit human hCART1 nuclear localization and human endogenous ALX1 chromatin occupancy. No ALX1-specific loss of the inherited compartment is evident. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN004692309 SUPPORTS TRANSFER Human nuclear localization directly corroborates the inherited compartment; no original IBD reconstruction claimed. Supporting Evidence: PMID:9753625 It is also shown here that hCART1 localizes to nucleus. |
| GO:0005634 nucleus | IDA PMID:23288509 ALX1 induces snail expression to promote epithelial-to-mesen... | ACCEPT | Summary: ALX1 acts in the nucleus in its transcriptional role. Reason: The source reports human ALX1-dependent SNAI1 promoter regulation in ovarian cancer models. Its nuclear IDA is retained with direct independent human localization from PMID:9753625; the nuclear Snail image in Figure 5 is not relabeled as an ALX1 localization assay. Supporting Evidence: PMID:9753625 It is also shown here that hCART1 localizes to nucleus. PMID:23288509 We found that ALX1 upregulated expression of the key EMT regulator Snail (SNAI1) and that it mediated EMT activation and cell invasion by ALX1. |
| GO:0005634 nucleus | IDA PMID:9753625 Human CART1, a paired-class homeodomain protein, activates t... | ACCEPT | Summary: The original human study explicitly reports nuclear hCART1 localization. Reason: PMID:9753625 directly reports nuclear localization alongside HeLa transcription assays. The statement is about the human protein, not only a rodent homolog. Supporting Evidence: PMID:9753625 It is also shown here that hCART1 localizes to nucleus. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: The combined automated nuclear location is biologically sound. Reason: The source combines mouse Alx1/Compara and the UniProt nuclear location mapping SL-0191. Direct human hCART1 localization independently supports the same compartment. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C8B0 SUPPORTS TRANSFER The mouse Alx1 source and UniProt nuclear-location mapping agree with direct human localization; no compartment-transfer failure demonstrated. Supporting Evidence: PMID:9753625 It is also shown here that hCART1 localizes to nucleus. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence supports nucleoplasmic ALX1. Reason: Archived HPA v22 reports supported nucleoplasmic ALX1 immunofluorescence with antibody HPA001598 in HEK293, U-251MG and U2OS cells. This is direct human subnuclear evidence for the observed cell-line panel, without implying uniform staining in all tissues. The attributed HPA excerpt and primary URL are preserved in the notes. Supporting Evidence: file:human/ALX1/ALX1-notes.md Nucleoplasm (supported), Golgi apparatus (uncertain) |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000107 | ACCEPT | Summary: Retain participation in a transcription regulator complex at the broad transferred scope. Reason: The mouse Alx1 Compara source is consistent with Cart1–p300/CBP physical and transcriptional coupling in the structured primary abstract of PMID:12929931. Human ALX1 additionally co-occupies developmental regulatory chromatin with cooperating factors in PMID:38262408. GO:0005667 permits a functional DNA-associated transcription-regulating assembly; a fixed soluble stoichiometry is not required by its definition. The full donor construct/host details and exact transferred experiment were not recovered, so no specific human p300 complex, purified ALX1 ternary structure or invariant stoichiometry is asserted. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C8B0 SUPPORTS TRANSFER Mouse Alx1 donor identity is verified; primary Cart1/coactivator association and conserved human transcriptional assembly context support the broad complex transfer, while exact donor assay details remain bounded. Supporting Evidence: PMID:12929931 Cart1 binds to p300 in vivo and in vitro PMID:38262408 Together these data indicate that TWIST1 can bind Coordinator sites with multiple HD TFs including ALX4, ALX1, MSX1, and PRRX1 |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: DNA-templated transcriptional regulation is a central ALX1 function. Reason: The IPR017970 mapping is supported by positive and negative human promoter assays. The broad process remains true and core even though more specific signed Pol II annotations also exist. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR017970 SUPPORTS TRANSFER Human promoter experiments corroborate transcriptional regulation; no mapping failure is demonstrated. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. PMID:8756334 Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. |
| GO:0010718 positive regulation of epithelial to mesenchymal transition | IMP PMID:23288509 ALX1 induces snail expression to promote epithelial-to-mesen... | KEEP AS NON CORE | Summary: ALX1 promotes EMT through transcriptional induction of SNAI1 in studied cancer models. Reason: The original human ovarian cancer study shows ALX1 gain/loss effects, SNAI1 promoter reporter regulation and Snail epistasis, providing regulatory participation beyond a loss phenotype. Indexed original Results/Figure 5 distinguish SKOV3/HEY responses from an ES2 context without the same SNAI1 response. This is a context-specific transcriptional output, not a universal developmental EMT function or a separate intrinsic catalytic activity. Supporting Evidence: PMID:23288509 We found that ALX1 upregulated expression of the key EMT regulator Snail (SNAI1) and that it mediated EMT activation and cell invasion by ALX1. |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | ACCEPT | Summary: HPA supports ALX1 localization in nuclear bodies. Reason: Archived HPA v22 reports supported nuclear-body ALX1 staining with HPA001598 in HEK293, U-251MG and U2OS cells, providing the direct human evidence. The PMID:12929931 abstract additionally reports Cart1-dependent p300 recruitment to a subnuclear compartment, but does not establish the Cart1 construct species or host in the accessible text; this is corroboration, not a human-specific endogenous ALX1 assay. No named body subtype, invariant association or Golgi function is inferred. Supporting Evidence: file:human/ALX1/ALX1-notes.md Nuclear bodies (supported) PMID:12929931 Confocal microscopy analysis shows that Cart1 recruits overexpressed and endogenous p300 to a Cart1-specific subnuclear compartment. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Conserved sequence-selective DNA binding is directly confirmed in human ALX1. Reason: The mouse Alx1 Compara source is corroborated by human oligonucleotide selection and recombinant hCART1 EMSA. This existing binding assertion captures sequence recognition within the same transcriptional mechanism; no new redundant binding annotation is added. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C8B0 SUPPORTS TRANSFER Verified mouse Alx1 ortholog; direct human sequence selection/EMSA supports the target activity independently. Supporting Evidence: PMID:9753625 It is reported here that all sites obtained contain a palindrome consisting of two TAAT sequences separated by three or four base pairs. |
| GO:0045892 negative regulation of DNA-templated transcription | IBA GO_REF:0000033 | ACCEPT | Summary: Promoter-specific repression is a conserved component of ALX1 transcriptional regulation. Reason: The PTN002803087 ancestral assertion agrees with human hCART1 repression through the prolactin footprint II site. Human Q15699 in the descendant evidence is legitimate grounding. The positive activator annotations concern different promoters/contexts and do not invert this regulatory sign. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002803087 SUPPORTS TRANSFER Direct human negative promoter regulation supports the inherited repression assertion; exact ancestral IBD reconstruction not claimed. Supporting Evidence: PMID:8756334 Cotransfection studies show that Cart-1 inhibits the rat prolactin promoter and that this repression is mediated by footprint II, an AT-rich element that functions as an inhibitory site of prolactin gene expression in nonpituitary cells and which was used to clone Cart-1. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:9753625 Human CART1, a paired-class homeodomain protein, activates t... | ACCEPT | Summary: Human ALX1 positively regulates transcription through selected binding sites. Reason: The original hCART1 study directly measures sequence- and dose-dependent reporter activation in HeLa cells. Broad positive DNA-templated regulation is retained as part of the core transcriptional function. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:23288509 ALX1 induces snail expression to promote epithelial-to-mesen... | ACCEPT | Summary: ALX1 positively regulates SNAI1 expression in responsive human cell models. Reason: PMID:23288509 connects ALX1 expression/attenuation to SNAI1 RNA and protein and shows SNAI1 promoter reporter effects. This is direct evidence of transcriptional regulation, although promoter occupancy by ALX1 was not independently demonstrated in the inspected experiments. The generic positive transcription process fits the core mechanism; the cancer-specific EMT consequence is separately non-core. Supporting Evidence: PMID:23288509 We found that ALX1 upregulated expression of the key EMT regulator Snail (SNAI1) and that it mediated EMT activation and cell invasion by ALX1. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Positive Pol II transcriptional regulation is supported by human target assays. Reason: PTN002803087 transfer is consistent with the direct human hCART1 reporter study and endogenous human developmental transcriptional regulation in PMID:38262408. The target appearing in PAINT evidence is expected and not circular; activation is promoter-dependent. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002803087 SUPPORTS TRANSFER Human reporter activation supplies direct descendant evidence consistent with the inherited positive Pol II process. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:9753625 Human CART1, a paired-class homeodomain protein, activates t... | ACCEPT | Summary: Human ALX1 activates Pol II reporter transcription. Reason: The original human hCART1 binding-site reporter assays establish site- and dosage-dependent transcriptional activation in HeLa cells. This provides an explicit functional basis for the Pol II process annotation. Supporting Evidence: PMID:9753625 In transient transfection assays, hCART1 activates transcription from reporter plasmids containing hCART1 binding sites in HeLa cells, demonstrating both site-dependence and dosage-dependence. |
| GO:0048666 neuron development | IBA GO_REF:0000033 | UNDECIDED | Summary: The neuron-development ancestral assertion remains unresolved for human ALX1. Reason: GO:0048666 concerns progression of a neuron toward its mature functional state. The inspected ALX1 sources establish cranial mesenchyme, neural crest migration, neural tube closure and craniofacial patterning; those are not themselves an assay of neuronal maturation. However, they do not disprove an additional neuronal role. The PTN001216073 IBD placement and relevant descendant experiments were not independently recovered, so family-level descriptions or donor counts cannot justify rejecting the curator assertion. The electronic family summary is explicitly machine-generated and is not treated as primary neuronal evidence. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001216073 UNRESOLVED Original ancestral placement and neuron-maturation descendant assays were not recovered. Mesenchymal/neural-crest evidence cannot settle the separate neuronal assertion. Supporting Evidence: PMID:8673125 Cart1 is required for forebrain mesenchyme survival PMID:32914578 a lack of understanding which stage of development the NCC represent. |
| GO:0048704 embryonic skeletal system morphogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: ALX1 transcriptional regulation contributes to embryonic craniofacial skeletal patterning. Reason: The PTN002803087 skeletal-morphogenesis assertion is supported by mouse craniofacial skeletal malformations in PMID:35127681 and human ALX1 disease in PMID:20451171. Direct regulatory participation is supplied by endogenous ALX1 occupancy in human cranial neural crest cells together with ALX1 depletion-dependent chromatin accessibility and anterior facial transcriptional changes in PMID:38262408. ALX1 performs regulatory work through its DNA-binding transcription factor activity. The long-term perturbations can include indirect effects; combined ALX1/ALX4 effects are not assigned wholly to ALX1, and the paper's purified structural work tests ALX4. The integrated core therefore includes this existing broad skeletal-patterning process without a new annotation or a separate molecular function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002803087 SUPPORTS TRANSFER Mouse Alx1 craniofacial phenotype and direct conserved human transcriptional function support the existing developmental transfer; no claim to reconstruct the exact ancestral node. Supporting Evidence: PMID:35127681 embryos had hypoplastic premaxilla and presphenoid bone, and malformed palatal processes PMID:20451171 In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene PMID:38262408 However, the strength of ChIP signal is reproducibly distinct between the tagged HD TFs, with strongest signal for ALX1. PMID:38262408 ALX1 depletion results in significant changes in accessibility at 6,195 peaks (FDR < 0.05) PMID:38262408 This suggests that ALXs promote expression of genes associated with this anterior identity, as seen in a recent Alx1-null mouse37. |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: Sequence-specific double-stranded DNA recognition is independently established. Reason: The original human-TF methylation/SELEX source is authentic, but its local full_text_available metadata accompanies a partial HTML extraction and the ALX1-specific supplement was not inspected. The exact biochemical function is directly corroborated by recombinant human hCART1 EMSA and site selection (PMID:9753625), so retain the curator annotation without claiming a verified ALX1 methyl-CpG preference or reassigning another TF result. Supporting Evidence: PMID:9753625 It is reported here that all sites obtained contain a palindrome consisting of two TAAT sequences separated by three or four base pairs. |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: The electronic sequence-specific DNA-binding assertion agrees with direct human assays. Reason: ARBA00028376 predicts a property demonstrated by human hCART1 sequence selection and recombinant EMSA. The rule was not independently reconstructed, but its target assertion is biologically supported; no novel or redundant binding term is proposed. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028376 SUPPORTS TRANSFER Direct human sequence-selective DNA binding corroborates the rule output; no evidence of target-specific loss. Supporting Evidence: PMID:9753625 It is reported here that all sites obtained contain a palindrome consisting of two TAAT sequences separated by three or four base pairs. |
Loading supporting content…
Download this section (compressed HTML)Q: Which physiological ALX1 cofactors and regulatory DNA architectures determine activation versus repression in human craniofacial mesenchymal lineages?
Q: Does human ALX1 form an obligatory DNA-bound homodimer, or do its oligomeric partners and stoichiometry vary across endogenous regulatory sites?
Q: Which ancestral-clade experiments support the PAINT neuron-development assertion, and does ALX1 regulate neuronal maturation independently of its neural crest and cranial mesenchyme functions?
Q: Which curated ALX1 interaction partners have a reproducible physiological role in its nuclear localization or transcriptional regulation, beyond pairwise high-throughput detection?
Q: How does the early mouse cranial-mesoderm requirement for Alx1 relate to human extraocular muscle development and ALX1-associated disease?
Q: Which Cart1 species and constructs underlie the p300/CBP interaction in PMID:12929931, and do matched human ALX1 assays establish a specific cofactor-binding function and its physiological transcriptional context?
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)