cudA

id: O00841
gene_symbol: cudA
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: CudA is a nuclear, sequence-specific DNA-binding transcription factor
  of the social amoeba Dictyostelium discoideum that is essential for normal
  culmination and for the differentiation of both prestalk and prespore cells. It
  is the founding member of a novel family of transcription factors (the CudA/PTS
  family) whose conserved central core region constitutes a presumptive
  DNA-binding domain that is structurally related to the DNA-binding region of
  plant STAT-like proteins. CudA binds an interrupted dyad element containing GAA
  half-sites and forms homodimers, and it directly activates target genes such as
  the cotC spore-coat gene in prespore cells and the expansin-like expl7 gene in
  the slug tip-organiser. CudA is expressed in the nuclei of the prestalk cells of
  the slug tip (the tip-organiser/pstA cells) and in prespore cells, and its
  tip-specific expression is induced by the STATa signalling pathway acting
  downstream of the ACA adenylyl cyclase. Cells lacking cudA fail to culminate,
  continue to migrate as slugs under conditions where wild-type slugs culminate,
  and are defective in both mature stalk and mature spore formation.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of nuclear localization is correct and strongly
      corroborated by direct experimental evidence; CudA is a nuclear transcription
      factor.
    action: ACCEPT
    reason: CudA is directly shown to be a nucleoplasmic/nuclear protein that binds
      chromatin (cotC promoter) in vivo, so the IBA nuclear annotation is fully
      consistent with the experimental data.
    supported_by:
    - reference_id: PMID:19757394
      supporting_text: CudA is a nuclear protein which is expressed in prespore
        cells where it acts as a specific transcription factor.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: CudA is a sequence-specific DNA-binding transcription factor that
      regulates gene expression, so the general transcription-regulation term is
      appropriate. Direct evidence specifically supports a positive (activator)
      role.
    action: ACCEPT
    reason: The IBA inference that CudA is involved in regulation of transcription
      is confirmed experimentally; CudA binds target promoters and controls their
      expression. The general term is correct; the more specific activator role is
      captured in the core functions and in the positive-regulation annotations.
    supported_by:
    - reference_id: PMID:19757394
      supporting_text: STATa then induces expression of cudA and cudA directs the
        transcription of target genes such as expl7.
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Sequence-specific DNA binding is a core molecular function of CudA and
      is directly demonstrated experimentally; the IBA inference is well supported.
    action: ACCEPT
    reason: CudA binds a defined interrupted-dyad sequence in target promoters, as
      shown by DNA affinity chromatography, ChIP, and band-shift analysis. The IBA
      annotation matches the experimental evidence.
    supported_by:
    - reference_id: PMID:18701541
      supporting_text: We conclude that the dyad, defined using ECudA, also forms
        part or all of a CudA binding site.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular-location mapping to nucleoplasm is correct and
      matches direct experimental evidence describing CudA as a nucleoplasmic
      protein.
    action: ACCEPT
    reason: CudA was originally characterized as a nucleoplasmic protein, so the
      IEA nucleoplasm annotation derived from the UniProt subcellular location is
      accurate.
    supported_by:
    - reference_id: PMID:9226443
      supporting_text: The Dictyostelium cudA gene encodes a nucleoplasmic protein
        that is essential for normal culmination.
- term:
    id: GO:0097696
    label: cell surface receptor signaling pathway via STAT
  evidence_type: IMP
  original_reference_id: PMID:10821768
  qualifier: acts_upstream_of_or_within
  review:
    summary: CudA is the principal transcriptional effector/target of the STATa
      signalling pathway; STATa binds the cudA promoter and directly activates cudA
      transcription in prestalk cells. CudA thus acts within the STATa pathway as a
      downstream node, but this is not its core molecular function.
    action: KEEP_AS_NON_CORE
    reason: The annotation reflects that CudA operates downstream of STATa
      signalling (STATa is a direct activator of cudA), which is an experimentally
      supported and biologically meaningful placement within the pathway. It is,
      however, a pathway-level/developmental involvement rather than CudA's core
      transcription-factor activity.
    supported_by:
    - reference_id: PMID:10821768
      supporting_text: Dd-STATa appears therefore to serve as a direct activator of
        cudA transcription in prestalk cells
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:27125566
  qualifier: acts_upstream_of_or_within
  review:
    summary: CudA acts as a positive regulator of gene expression, directly
      activating downstream target genes such as expL7 in prestalk cells. This is a
      direct consequence of its core transcription-factor activity.
    action: ACCEPT
    reason: The abstract explicitly states that CudA directly activates expL7 gene
      expression, supporting positive regulation of gene expression as a genuine and
      central role of this activator.
    supported_by:
    - reference_id: PMID:27125566
      supporting_text: The only verified upregulated target gene of STATa is cudA
        gene; CudA directly activates expL7 gene expression in prestalk cells.
- term:
    id: GO:0031154
    label: culmination involved in sorocarp development
  evidence_type: IEP
  original_reference_id: PMID:25887420
  qualifier: acts_upstream_of_or_within
  review:
    summary: This annotation is inferred from the expression pattern of cudA, which
      is sharply up-regulated during late (slug-to-culmination) development. The
      involvement of cudA in culmination is well established genetically, but this
      particular annotation rests only on expression timing.
    action: KEEP_AS_NON_CORE
    reason: The expression-based (IEP) evidence corroborates a developmental role in
      culmination but is weaker than the mutant-based evidence, and culmination is a
      downstream developmental process rather than CudA's core molecular function.
    supported_by:
    - reference_id: PMID:25887420
      supporting_text: At 16 h, cudA and mybE were up-regulated sharply
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:19757394
  qualifier: acts_upstream_of_or_within
  review:
    summary: CudA is required for expression of its target gene expl7; expl7 is not
      expressed in cudA-null slugs, and CudA binds the expl7 promoter, establishing
      CudA as a positive transcriptional regulator.
    action: ACCEPT
    reason: Loss of cudA abolishes expl7 expression and CudA binds the expl7
      promoter, providing strong support for a positive regulatory role over gene
      expression. This directly reflects CudA's activator function.
    supported_by:
    - reference_id: PMID:19757394
      supporting_text: there is no detectable expression of expl7 in cudA null slugs
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19757394
  qualifier: enables
  review:
    summary: Direct evidence shows CudA binds a defined region (region B) of the
      expl7 promoter by DNA affinity chromatography of slug nuclear extracts.
    action: ACCEPT
    reason: CudA from slug nuclear extracts binds specifically to a defined promoter
      fragment, directly supporting sequence-specific DNA binding as a core
      molecular function.
    supported_by:
    - reference_id: PMID:19757394
      supporting_text: Region B binds CudA
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:18701541
  qualifier: enables
  review:
    summary: CudA binds a specific interrupted-dyad element in the cotC promoter, as
      shown by in vivo ChIP and by DNA affinity chromatography; a conserved core
      domain constitutes the presumptive DNA-binding domain and CudA forms a
      homodimer consistent with the dyad binding site.
    action: ACCEPT
    reason: This is the strongest evidence for sequence-specific DNA binding; in
      vivo promoter occupancy (ChIP), affinity chromatography, and mutational
      mapping of the binding site all support this core molecular function.
    supported_by:
    - reference_id: PMID:18701541
      supporting_text: We conclude that the dyad, defined using ECudA, also forms
        part or all of a CudA binding site.
    - reference_id: PMID:18701541
      supporting_text: Thus, CudA is bound at the promoter of the cotC gene.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: PMID:9226443
  qualifier: located_in
  review:
    summary: CudA was directly characterized as a nucleoplasmic protein, supporting
      this localization annotation.
    action: ACCEPT
    reason: Direct experimental evidence from the founding cudA study describes CudA
      as a nucleoplasmic protein, consistent with its role as a transcription factor.
    supported_by:
    - reference_id: PMID:9226443
      supporting_text: The Dictyostelium cudA gene encodes a nucleoplasmic protein
        that is essential for normal culmination.
- term:
    id: GO:0030435
    label: sporulation resulting in formation of a cellular spore
  evidence_type: IMP
  original_reference_id: PMID:9226443
  qualifier: involved_in
  review:
    summary: cudA-null cells are defective in spore formation, indicating that CudA
      is required for normal sporulation. This is a downstream developmental outcome
      of CudA's role as a prespore-gene transcriptional activator.
    action: KEEP_AS_NON_CORE
    reason: The mutant phenotype supports a genuine requirement for cudA in spore
      formation, but sporulation is a pleiotropic developmental process that follows
      from CudA's core transcription-factor activity rather than being that core
      function itself.
    supported_by:
    - reference_id: PMID:9226443
      supporting_text: cudA- mutant cells are indeed defective in both stalk and
        spore formation.
- term:
    id: GO:0031154
    label: culmination involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:9226443
  qualifier: involved_in
  review:
    summary: cudA is essential for normal culmination; cudA-null slugs continue to
      migrate under conditions where wild-type slugs culminate, and cudA was
      identified precisely as a culmination-deficient mutant.
    action: KEEP_AS_NON_CORE
    reason: The requirement for cudA in culmination is strongly supported by mutant
      phenotype, but culmination is a downstream developmental process controlled by
      CudA's transcriptional activity rather than its core molecular function.
    supported_by:
    - reference_id: PMID:9226443
      supporting_text: The Dictyostelium cudA gene encodes a nucleoplasmic protein
        that is essential for normal culmination.
    - reference_id: PMID:9226443
      supporting_text: the slugs formed by cudA- cells continue to migrate under
        environmental conditions where normal slugs culminate immediately
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:9226443
  qualifier: located_in
  review:
    summary: CudA is directly localized to the nucleus (nucleoplasm), consistent
      with its function as a DNA-binding transcription factor.
    action: ACCEPT
    reason: Direct evidence establishes CudA as a nuclear/nucleoplasmic protein, so
      the nucleus localization annotation is accurate.
    supported_by:
    - reference_id: PMID:9226443
      supporting_text: The Dictyostelium cudA gene encodes a nucleoplasmic protein
        that is essential for normal culmination.
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:9226443
  qualifier: acts_upstream_of_or_within
  review:
    summary: CudA is required for the differentiation of both stalk and spore cells,
      acting on both pathways of cell-type differentiation as a transcriptional
      regulator.
    action: KEEP_AS_NON_CORE
    reason: The mutant is defective in both stalk and spore differentiation,
      supporting a role in cell differentiation. This is, however, a very general
      developmental-process term downstream of CudA's core transcription-factor
      activity; the more specific developmental roles are captured by the
      culmination and sporulation annotations.
    supported_by:
    - reference_id: PMID:9226443
      supporting_text: This unusual pattern of expression suggests a role on both
        the stalk and spore pathways of differentiation
    - reference_id: PMID:9226443
      supporting_text: cudA- mutant cells are indeed defective in both stalk and
        spore formation.
- term:
    id: GO:0031154
    label: culmination involved in sorocarp development
  evidence_type: IMP
  original_reference_id: PMID:9226443
  qualifier: acts_upstream_of_or_within
  review:
    summary: Duplicate culmination annotation from the same study with a different
      qualifier; cudA is required for entry into culmination, a property of the
      tip-organiser cells in which CudA is expressed.
    action: KEEP_AS_NON_CORE
    reason: As with the other culmination annotation, this is strongly supported by
      the mutant phenotype but represents a downstream developmental process rather
      than CudA's core molecular function.
    supported_by:
    - reference_id: PMID:9226443
      supporting_text: the slugs formed by cudA- cells continue to migrate under
        environmental conditions where normal slugs culminate immediately
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:10821768
  title: Analysis of the promoter of the cudA gene reveals novel mechanisms of Dictyostelium
    cell type differentiation.
  findings:
  - statement: STATa directly activates cudA transcription in prestalk cells by
      binding an essential site in the prestalk-specific region of the cudA promoter.
    supporting_text: Dd-STATa appears therefore to serve as a direct activator of
      cudA transcription in prestalk cells
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only in cache; establishes that cudA is a direct
      transcriptional target of the STATa signalling pathway in prestalk cells and
      that distinct promoter elements drive prespore vs prestalk expression.
- id: PMID:18701541
  title: A new family of transcription factors.
  findings:
  - statement: CudA binds in vivo to the cotC prespore promoter and is required for
      prespore-specific gene expression.
    supporting_text: CudA, a nuclear protein required for Dictyostelium
      prespore-specific gene expression, binds in vivo to the promoter of the cotC
      prespore gene.
  - statement: CudA binds an interrupted dyad DNA element and forms a homodimer,
      consistent with a symmetrical binding site.
    supporting_text: consistent with a symmetrical binding site, CudA forms a
      homodimer in the yeast two-hybrid system
  - statement: CudA defines a new family of transcription factors whose conserved
      core region is a presumptive DNA-binding domain related to plant STAT-like
      proteins.
    supporting_text: This region, the presumptive DNA-binding domain, is similar in
      sequence to domains in two Arabidopsis proteins and one Oryza protein.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available (PMC3586674). Defines CudA sequence-specific
      DNA binding (ChIP plus affinity chromatography), homodimerization, and the
      conserved presumptive DNA-binding domain; founding paper for the CudA/PTS
      transcription-factor family.
- id: PMID:19757394
  title: Identification of a target for CudA, the transcription factor which directs
    formation of the Dictyostelium tip organiser.
  findings:
  - statement: CudA acts as a specific transcription factor in prespore cells and in
      the tip-organiser.
    supporting_text: CudA is a nuclear protein which is expressed in prespore cells
      where it acts as a specific transcription factor.
  - statement: CudA directly activates the tip-organiser gene expl7; expl7 is not
      expressed in cudA-null slugs and CudA binds the expl7 promoter.
    supporting_text: there is no detectable expression of expl7 in cudA null slugs
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available (PMC3672975). Identifies expl7 as a direct
      CudA target and places CudA downstream of ACA/STATa signalling in
      tip-organiser differentiation.
- id: PMID:25887420
  title: Leaps and lulls in the developmental transcriptome of Dictyostelium discoideum.
  findings:
  - statement: cudA transcript is sharply up-regulated at ~16 h, coincident with the
      slug/culmination phase of development.
    supporting_text: At 16 h, cudA and mybE were up-regulated sharply
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available (PMC4403905). Genome-wide developmental time
      course; cudA appears only as one of many late-development transcription
      factors, supporting expression timing but not mechanism.
- id: PMID:27125566
  title: Regulation of ecmF gene expression and genetic hierarchy among STATa, CudA,
    and MybC on several prestalk A-specific gene expressions in Dictyostelium.
  findings:
  - statement: cudA is the only verified up-regulated target gene of STATa, and CudA
      directly activates expL7 expression in prestalk cells.
    supporting_text: The only verified upregulated target gene of STATa is cudA gene;
      CudA directly activates expL7 gene expression in prestalk cells.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only in cache; supports CudA as a positive transcriptional
      regulator and defines CudA-dependent vs CudA-independent branches downstream
      of STATa.
- id: PMID:9226443
  title: 'cudA: a Dictyostelium gene with pleiotropic effects on cellular differentiation
    and slug behaviour.'
  findings:
  - statement: cudA encodes a nucleoplasmic protein essential for normal culmination.
    supporting_text: The Dictyostelium cudA gene encodes a nucleoplasmic protein
      that is essential for normal culmination.
  - statement: cudA-null cells are defective in both stalk and spore formation,
      indicating a role on both differentiation pathways.
    supporting_text: cudA- mutant cells are indeed defective in both stalk and spore
      formation.
  - statement: cudA-null slugs fail to enter culmination and continue migrating under
      conditions where wild-type slugs culminate.
    supporting_text: the slugs formed by cudA- cells continue to migrate under
      environmental conditions where normal slugs culminate immediately
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only in cache but this is the founding cudA study
      (insertional mutagenesis); establishes nucleoplasmic localization, culmination
      requirement, pleiotropic differentiation phenotype, and tip-organiser
      expression.
core_functions:
- description: CudA is a sequence-specific DNA-binding transcription factor that
    binds an interrupted dyad element (with GAA half-sites) in the promoters of
    developmental target genes. Its conserved central core region is a presumptive
    DNA-binding domain and CudA binds DNA as a homodimer, occupying target promoters
    such as cotC in vivo.
  molecular_function:
    id: GO:0043565
    label: sequence-specific DNA binding
  directly_involved_in:
  - id: GO:0006355
    label: regulation of DNA-templated transcription
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005654
    label: nucleoplasm
  supported_by:
  - reference_id: PMID:18701541
    supporting_text: We conclude that the dyad, defined using ECudA, also forms part
      or all of a CudA binding site.
  - reference_id: PMID:18701541
    supporting_text: Thus, CudA is bound at the promoter of the cotC gene.
  - reference_id: PMID:18701541
    supporting_text: consistent with a symmetrical binding site, CudA forms a
      homodimer in the yeast two-hybrid system
- description: Acting through its sequence-specific DNA binding, CudA functions as a
    positive transcriptional regulator that directly activates cell-type-specific
    developmental target genes, including the cotC prespore spore-coat gene and the
    tip-organiser gene expl7. Loss of cudA abolishes expression of these targets.
  molecular_function:
    id: GO:0043565
    label: sequence-specific DNA binding
  directly_involved_in:
  - id: GO:0010628
    label: positive regulation of gene expression
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:19757394
    supporting_text: there is no detectable expression of expl7 in cudA null slugs
  - reference_id: PMID:27125566
    supporting_text: The only verified upregulated target gene of STATa is cudA gene;
      CudA directly activates expL7 gene expression in prestalk cells.
  - reference_id: PMID:18701541
    supporting_text: CudA, a nuclear protein required for Dictyostelium
      prespore-specific gene expression, binds in vivo to the promoter of the cotC
      prespore gene.