Details for: CITED4

Gene ID: 163732

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CITED4

Ensembl ID: ENSG00000179862

Description: Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • intrahepatic cholangiocyte CL0002538
    CSI 13.78
    rCSI 33.06%
    PRS 92.91
  • fallopian tube secretory epithelial cell CL4030006
    CSI 11.98
    rCSI 11.53%
    PRS 92
  • pancreatic ductal cell CL0002079
    CSI 11.43
    rCSI 22.23%
    PRS 94.26
  • vascular associated smooth muscle cell CL0000359
    CSI 10.32
    rCSI 33.46%
    PRS 91.76
  • common myeloid progenitor CL0000049
    CSI 8.53
    rCSI 6.9%
    PRS 94.14
  • fibroblast of lung CL0002553
    CSI 7.78
    rCSI 7.24%
    PRS 94.49
  • granulocyte monocyte progenitor cell CL0000557
    CSI 7.12
    rCSI 6.16%
    PRS 94.73
  • blood vessel endothelial cell CL0000071
    CSI 6.85
    rCSI 14.22%
    PRS 91.94
  • basal cell of prostate epithelium CL0002341
    CSI 6.13
    rCSI 17.73%
    PRS 94.78
  • interstitial cell of Cajal CL0002088
    CSI 6.11
    rCSI 7.78%
    PRS 95.69
  • pulmonary artery endothelial cell CL1001568
    CSI 5.68
    rCSI 7.73%
    PRS 96.35
  • secretory cell CL0000151
    CSI 5.12
    rCSI 5.34%
    PRS 92.39
  • ciliated cell CL0000064
    CSI 4.48
    rCSI 7.25%
    PRS 87.85
  • P/D1 enteroendocrine cell CL0002268
    CSI 3.97
    rCSI 21.59%
    PRS 94.77
  • mucus secreting cell CL0000319
    CSI 3.94
    rCSI 6.25%
    PRS 96.38
  • ciliated epithelial cell CL0000067
    CSI 3.93
    rCSI 3.46%
    PRS 85.88
  • group 3 innate lymphoid cell CL0001071
    CSI 3.9
    rCSI 2.93%
    PRS 95.27
  • enteroendocrine cell CL0000164
    CSI 3.79
    rCSI 5.17%
    PRS 91.37
  • perivascular cell CL4033054
    CSI 3.78
    rCSI 5.17%
    PRS 95.55
  • epithelial cell CL0000066
    CSI 3.63
    rCSI 5.57%
    PRS 82.39
  • CD4-positive helper T cell CL0000492
    CSI 3.42
    rCSI 2.59%
    PRS 98.14
  • stem cell CL0000034
    CSI 3.25
    rCSI 3.13%
    PRS 90.14
  • respiratory suprabasal cell CL4033048
    CSI 3.23
    rCSI 4.15%
    PRS 94.39
  • myoepithelial cell CL0000185
    CSI 3.17
    rCSI 8.02%
    PRS 94.81
  • promyelocyte CL0000836
    CSI 3.17
    rCSI 4.57%
    PRS 94.78
  • myofibroblast cell CL0000186
    CSI 3.15
    rCSI 4.36%
    PRS 90.61
  • glandular epithelial cell CL0000150
    CSI 3.02
    rCSI 7.95%
    PRS 97.64
  • pulmonary capillary endothelial cell CL4028001
    CSI 2.91
    rCSI 5.55%
    PRS 96.81
  • club cell CL0000158
    CSI 2.87
    rCSI 4.21%
    PRS 89.7
  • basal cell CL0000646
    CSI 2.65
    rCSI 3.54%
    PRS 90.78
  • pancreatic acinar cell CL0002064
    CSI 2.57
    rCSI 3.41%
    PRS 95.31
  • retinal pigment epithelial cell CL0002586
    CSI 2.55
    rCSI 5.05%
    PRS 90.44
  • ionocyte CL0005006
    CSI 2.53
    rCSI 2.71%
    PRS 94.09
  • endothelial cell of lymphatic vessel CL0002138
    CSI 2.53
    rCSI 5.01%
    PRS 93.65
  • keratinocyte CL0000312
    CSI 2.5
    rCSI 2.1%
    PRS 92.87
  • epithelial cell of proximal tubule CL0002306
    CSI 2.5
    rCSI 6.1%
    PRS 88.14
  • intestinal epithelial cell CL0002563
    CSI 2.41
    rCSI 2.51%
    PRS 91.18
  • multi-ciliated epithelial cell CL0005012
    CSI 2.4
    rCSI 2.4%
    PRS 88.29
  • duct epithelial cell CL0000068
    CSI 2.38
    rCSI 3.49%
    PRS 95.81
  • conjunctival epithelial cell CL1000432
    CSI 2.34
    rCSI 3.58%
    PRS 92.32
  • enteric smooth muscle cell CL0002504
    CSI 2.31
    rCSI 3.3%
    PRS 93.1
  • acinar cell CL0000622
    CSI 2.3
    rCSI 3.37%
    PRS 96.77
  • common dendritic progenitor CL0001029
    CSI 2.27
    rCSI 2.85%
    PRS 96.56
  • lung ciliated cell CL1000271
    CSI 2.25
    rCSI 2.6%
    PRS 88.77
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 2.17
    rCSI 4.94%
    PRS 87.12
  • promonocyte CL0000559
    CSI 2.16
    rCSI 3.7%
    PRS 94.5
  • endothelial cell of uterus CL0009095
    CSI 2.05
    rCSI 15.01%
    PRS 96.34
  • corneal epithelial cell CL0000575
    CSI 1.89
    rCSI 5.41%
    PRS 93.96
  • luminal epithelial cell of mammary gland CL0002326
    CSI 1.77
    rCSI 3.22%
    PRS 96.41
  • prostate gland microvascular endothelial cell CL2000059
    CSI 1.22
    rCSI 29.18%
    PRS 95.63
  • type EC enteroendocrine cell CL0000577
    CSI 1.06
    rCSI 3.75%
    PRS 94.06
  • microcirculation associated smooth muscle cell CL0008035
    CSI 0.99
    rCSI 2.86%
    PRS 92.61
  • acinar cell of salivary gland CL0002623
    CSI 0.96
    rCSI 22.29%
    PRS 96.72
  • luminal cell of prostate epithelium CL0002340
    CSI 0.86
    rCSI 4.6%
    PRS 95.93
  • epithelial cell of urethra CL1000296
    CSI 0.84
    rCSI 21.22%
    PRS 94.69
  • endothelial cell of placenta CL0009092
    CSI 0.75
    rCSI 3.71%
    PRS 95.58
  • myelocyte CL0002193
    CSI 0.68
    rCSI 4.47%
    PRS 96.93

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary **Overall**, Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 4 ([CITED4](/details-gene/163732)) is a protein-coding gene that functions as a transcriptional co-activator. It is known to interact with the general transcriptional co-activators CBP/p300 and specifically enhances the activity of the AP-2 (TFAP2) family of transcription factors ([Link](https://doi.org/10.1074/jbc.m110850200)). Expression data reveals its high significance in various glandular and ductal epithelial cells, including [intrahepatic cholangiocyte](/details-cell/CL0002538), [fallopian tube secretory epithelial cell](/details-cell/CL4030006), and [pancreatic ductal cell](/details-cell/CL0002079), suggesting a key role in maintaining the function of secretory tissues. Its expression is also noted in mesenchymal lineages like [vascular associated smooth muscle cell](/details-cell/CL0000359) and in hematopoietic progenitors, indicating a broader role in cellular differentiation and transcriptional regulation. ## Cellular Roles and Expression Landscape The expression profile of [CITED4](/details-gene/163732) highlights its importance as a transcriptional regulator primarily within specialized epithelial and mesenchymal cell types. The highest significance scores are observed in cells lining ducts and secretory organs, such as [intrahepatic cholangiocyte](/details-cell/CL0002538) (CSI: 13.78), [fallopian tube secretory epithelial cell](/details-cell/CL4030006) (CSI: 11.98), and [pancreatic ductal cell](/details-cell/CL0002079) (CSI: 11.43). This pattern suggests that [CITED4](/details-gene/163732) is integral to the transcriptional programs that define the identity and function of these glandular tissues. Beyond its role in mature epithelial cells, [CITED4](/details-gene/163732) also shows significant expression in progenitor cell populations, including [common myeloid progenitor](/details-cell/CL0000049) (CSI: 8.53) and [granulocyte monocyte progenitor cell](/details-cell/CL0000557) (CSI: 7.12). This implies a potential function in hematopoietic lineage commitment and differentiation. Furthermore, its notable expression in [vascular associated smooth muscle cell](/details-cell/CL0000359) (CSI: 10.32) and [fibroblast of lung](/details-cell/CL0002553) (CSI: 7.78) points to a functional role in mesenchymal cell biology, possibly related to tissue structure, repair, or signaling. ## Pathways and Molecular Function Functionally, [CITED4](/details-gene/163732) is annotated with [transcription coactivator activity](/details-ontologies/GO:0003713) and is localized to both the [nucleus](/details-ontologies/GO:0005634) and [cytoplasm](/details-ontologies/GO:0005737), which is consistent with a role as a regulatory protein that may shuttle between compartments. Its involvement in the [positive regulation of dna-templated transcription](/details-ontologies/GO:0045893) is central to its function. Reactome pathway analysis confirms its role in fundamental transcriptional processes, including [Gene expression (transcription)](https://reactome.org/content/detail/R-HSA-74160) and [Rna polymerase ii transcription](https://reactome.org/content/detail/R-HSA-73857). More specifically, it is a key component of the [Transcriptional regulation by the ap-2 (tfap2) family of transcription factors](https://reactome.org/content/detail/R-HSA-8864260) pathway. This function aligns with its high expression in epithelial cells, where TFAP2 factors are critical for development and differentiation. The annotation for [response to estrogen](/details-ontologies/GO:0043627) is particularly relevant given its high significance in [fallopian tube secretory epithelial cell](/details-cell/CL4030006), a hormone-responsive cell type. In cancer biology, [CITED4](/details-gene/163732) has been shown to inhibit hypoxia-activated transcription, and its subcellular localization can be altered in disease states ([Link](https://doi.org/10.1158/0008-5472.can-04-0708)). ## Research Directions The functional profile of [CITED4](/details-gene/163732) as a transcriptional coactivator with distinct expression patterns and a complex role in cancer suggests several avenues for future research. **Proposed Hypotheses:** 1. Given its high expression in ductal epithelia ([intrahepatic cholangiocyte](/details-cell/CL0002538), [pancreatic ductal cell](/details-cell/CL0002079)) and its role as a TFAP2 co-activator, [CITED4](/details-gene/163732) is a critical factor for maintaining lineage identity and secretory function in these tissues. Its dysregulation may be a key event in the pathogenesis of diseases like cholangiocarcinoma or pancreatitis. 2. The subcellular localization of [CITED4](/details-gene/163732) acts as a regulatory switch for its function. In the nucleus, it co-activates TFAP2-mediated transcription, while its sequestration in the cytoplasm, as observed in some cancers ([Link](https://doi.org/10.1158/0008-5472.can-04-0708)), serves to inhibit hypoxia-inducible factor (HIF-1alpha) signaling, thereby linking transcriptional regulation to the cellular stress response. 3. The significant expression of [CITED4](/details-gene/163732) in [common myeloid progenitor](/details-cell/CL0000049)s suggests it plays a role in regulating the balance between self-renewal and differentiation during myelopoiesis, possibly by modulating the expression of key hematopoietic fate-determining genes. **Experimental Approach:** To test the hypothesis that the subcellular localization of [CITED4](/details-gene/163732) dictates its functional output (Hypothesis 2), a series of molecular cell biology experiments could be performed. A pancreatic ductal adenocarcinoma (PDAC) cell line, where [CITED4](/details-gene/163732) is endogenously expressed, could be engineered using CRISPR-Cas9 to knock out the native gene. Subsequently, cells would be reconstituted with expression vectors for either wild-type [CITED4](/details-gene/163732), a variant with a strong nuclear localization signal (NLS), or a variant with a nuclear export signal (NES) to enforce cytoplasmic retention. The impact of these variants on the transcriptional landscape under both normoxic and hypoxic conditions would be assessed by RNA-seq, focusing on TFAP2 and HIF-1 target gene signatures. Protein-protein interactions could be validated by co-immunoprecipitation followed by mass spectrometry to confirm whether nuclear [CITED4](/details-gene/163732) preferentially binds CBP/p300 and TFAP2, while cytoplasmic [CITED4](/details-gene/163732) interacts with components of the HIF-1 signaling pathway. **Therapeutic Potential:** Directly targeting a transcriptional co-activator like [CITED4](/details-gene/163732) with small molecules is challenging. However, its context-dependent role in cancer suggests it may serve as a valuable biomarker. For example, the ratio of nuclear to cytoplasmic [CITED4](/details-gene/163732) in tumor biopsies, as determined by immunohistochemistry, could be a prognostic marker or a predictor of response to therapies targeting the HIF pathway. If its cytoplasmic accumulation and subsequent inhibition of HIF signaling prove to be a tumor-suppressive mechanism, therapeutic strategies aimed at promoting its cytoplasmic retention could be explored, although this would represent a complex and novel approach. Therefore, its immediate value appears to be more as a biomarker than a direct drug target.

Genular Protein ID: 3949696189

Symbol: CITE4_HUMAN

Name: Cbp/p300-interacting transactivator 4

UniProtKB Accession Codes:

Q96RK1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 Ensembl 1 GO 5 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 STRING 1 SignaLink 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 11744733

Title: Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2.

PubMed ID: 11744733

DOI: 10.1074/jbc.m110850200

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15342390

Title: CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1alpha.

PubMed ID: 15342390

DOI: 10.1158/0008-5472.can-04-0708

Sequence Information:

  • Length: 184
  • Mass: 18569
  • Checksum: 6775E3F2F0C25F10
  • Sequence:
    • MADHLMLAEG YRLVQRPPSA AAAHGPHALR TLPPYAGPGL DSGLRPRGAP LGPPPPRQPG 
ALAYGAFGPP SSFQPFPAVP PPAAGIAHLQ PVATPYPGRA AAPPNAPGGP PGPQPAPSAA 
APPPPAHALG GMDAELIDEE ALTSLELELG LHRVRELPEL FLGQSEFDCF SDLGSAPPAG 
SVSC