Details for: NOL3

Gene ID: 8996

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: NOL3

Ensembl ID: ENSG00000140939

Description: nucleolar protein 3

Cell Significance Landscape

Associated with

  • Blood vessel remodeling
    (GO:0001974)
  • Calcium ion binding
    (GO:0005509)
  • Cardiac muscle cell apoptotic process
    (GO:0010659)
  • Caspase binding
    (GO:0089720)
  • Cysteine-type endopeptidase inhibitor activity involved in apoptotic process
    (GO:0043027)
  • Cytoplasm
    (GO:0005737)
  • Cytosol
    (GO:0005829)
  • Death receptor binding
    (GO:0005123)
  • Identical protein binding
    (GO:0042802)
  • Inhibition of cysteine-type endopeptidase activity involved in apoptotic process
    (GO:1990001)
  • Intrinsic apoptotic signaling pathway
    (GO:0097193)
  • Membrane
    (GO:0016020)
  • Mitochondrion
    (GO:0005739)
  • Mrna splice site recognition
    (GO:0006376)
  • Negative regulation of apoptotic process
    (GO:0043066)
  • Negative regulation of cardiac muscle cell apoptotic process
    (GO:0010667)
  • Negative regulation of extrinsic apoptotic signaling pathway
    (GO:2001237)
  • Negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway
    (GO:1903298)
  • Negative regulation of intrinsic apoptotic signaling pathway
    (GO:2001243)
  • Negative regulation of mitochondrial membrane permeability involved in apoptotic process
    (GO:1902109)
  • Negative regulation of muscle atrophy
    (GO:0014736)
  • Negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
    (GO:1902176)
  • Negative regulation of programmed necrotic cell death
    (GO:0062099)
  • Negative regulation of release of cytochrome c from mitochondria
    (GO:0090201)
  • Negative regulation of tumor necrosis factor-mediated signaling pathway
    (GO:0010804)
  • Nucleolus
    (GO:0005730)
  • Protein binding
    (GO:0005515)
  • Protein complex oligomerization
    (GO:0051259)
  • Regulation of non-canonical nf-kappab signal transduction
    (GO:1901222)
  • Release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    (GO:0014808)
  • Response to hypoxia
    (GO:0001666)
  • Response to injury involved in regulation of muscle adaptation
    (GO:0014876)
  • Response to ischemia
    (GO:0002931)
  • Rna binding
    (GO:0003723)
  • Rna splicing
    (GO:0008380)
  • Sarcoplasmic reticulum
    (GO:0016529)

Significant Cells

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

  • epithelial cell of lung CL0000082
    CSI 9.23
    rCSI 7.65%
    PRS 80.36
  • glial cell CL0000125
    CSI 6.5
    rCSI 24.75%
    PRS 70.94
  • neural progenitor cell CL0011020
    CSI 5.56
    rCSI 24.47%
    PRS 68.29
  • retinal ganglion cell CL0000740
    CSI 5.3
    rCSI 11.71%
    PRS 65.6
  • lung secretory cell CL1000272
    CSI 4.8
    rCSI 11.87%
    PRS 79.4
  • melanocyte CL0000148
    CSI 4.53
    rCSI 3.35%
    PRS 73.32
  • perivascular cell CL4033054
    CSI 4.33
    rCSI 5.92%
    PRS 84.09
  • type B pancreatic cell CL0000169
    CSI 4.28
    rCSI 9.48%
    PRS 79.12
  • microcirculation associated smooth muscle cell CL0008035
    CSI 4.14
    rCSI 11.98%
    PRS 79.26
  • epithelial cell of lower respiratory tract CL0002632
    CSI 3.86
    rCSI 2.99%
    PRS 83.34
  • Mueller cell CL0000636
    CSI 3.46
    rCSI 7.89%
    PRS 71.36
  • pancreatic D cell CL0000173
    CSI 3.4
    rCSI 3.34%
    PRS 82.32
  • myofibroblast cell CL0000186
    CSI 3.25
    rCSI 4.5%
    PRS 77.14
  • intestine goblet cell CL0019031
    CSI 2.92
    rCSI 2.6%
    PRS 77.37
  • ionocyte CL0005006
    CSI 2.89
    rCSI 3.09%
    PRS 80.98
  • ON-bipolar cell CL0000749
    CSI 2.88
    rCSI 4.27%
    PRS 79.84
  • OFF-bipolar cell CL0000750
    CSI 2.87
    rCSI 3.93%
    PRS 81.93
  • muscle cell CL0000187
    CSI 2.77
    rCSI 5.69%
    PRS 89
  • epithelial cell CL0000066
    CSI 2.74
    rCSI 4.21%
    PRS 69.36
  • keratinocyte CL0000312
    CSI 2.66
    rCSI 2.23%
    PRS 82.63
  • pancreatic A cell CL0000171
    CSI 2.62
    rCSI 2.75%
    PRS 83.02
  • pulmonary ionocyte CL0017000
    CSI 2.61
    rCSI 3.17%
    PRS 86.13
  • myoepithelial cell CL0000185
    CSI 2.53
    rCSI 6.39%
    PRS 84.94
  • retina horizontal cell CL0000745
    CSI 2.51
    rCSI 3.83%
    PRS 76.58
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.51
    rCSI 3.12%
    PRS 59.77
  • vascular associated smooth muscle cell CL0000359
    CSI 2.47
    rCSI 8%
    PRS 77.91
  • retinal bipolar neuron CL0000748
    CSI 2.43
    rCSI 4.56%
    PRS 68.26
  • tracheobronchial smooth muscle cell CL0019019
    CSI 2.43
    rCSI 4.29%
    PRS 84.88
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 2.43
    rCSI 2.94%
    PRS 60.88
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.36
    rCSI 5.29%
    PRS 62.6
  • rod bipolar cell CL0000751
    CSI 2.26
    rCSI 4.06%
    PRS 73.17
  • respiratory basal cell CL0002633
    CSI 2.23
    rCSI 2.31%
    PRS 83.91
  • retinal pigment epithelial cell CL0002586
    CSI 2.22
    rCSI 4.41%
    PRS 75.59
  • lung neuroendocrine cell CL1000223
    CSI 2.17
    rCSI 3.21%
    PRS 83.61
  • mucus secreting cell CL0000319
    CSI 2.1
    rCSI 3.34%
    PRS 88.11
  • conjunctival epithelial cell CL1000432
    CSI 2.04
    rCSI 3.11%
    PRS 80.01
  • intrahepatic cholangiocyte CL0002538
    CSI 2.04
    rCSI 4.88%
    PRS 83.68
  • peripheral nervous system neuron CL2000032
    CSI 2.02
    rCSI 2.75%
    PRS 71.39
  • retinal blood vessel endothelial cell CL0002585
    CSI 1.94
    rCSI 3.09%
    PRS 83.42
  • retinal rod cell CL0000604
    CSI 1.93
    rCSI 3.4%
    PRS 75.37
  • enteroendocrine cell CL0000164
    CSI 1.92
    rCSI 2.63%
    PRS 79.53
  • stem cell CL0000034
    CSI 1.91
    rCSI 1.84%
    PRS 72.96
  • club cell CL0000158
    CSI 1.9
    rCSI 2.79%
    PRS 74.28
  • extravillous trophoblast CL0008036
    CSI 1.79
    rCSI 2.22%
    PRS 77.52
  • retinal cone cell CL0000573
    CSI 1.73
    rCSI 2.79%
    PRS 69.82
  • lung pericyte CL0009089
    CSI 1.69
    rCSI 4.46%
    PRS 86.24
  • respiratory suprabasal cell CL4033048
    CSI 1.63
    rCSI 2.09%
    PRS 83.06
  • serous secreting cell CL0000313
    CSI 1.57
    rCSI 7.95%
    PRS 92.57
  • duct epithelial cell CL0000068
    CSI 1.54
    rCSI 2.25%
    PRS 84.45
  • pancreatic ductal cell CL0002079
    CSI 1.41
    rCSI 2.74%
    PRS 82.67
  • regular ventricular cardiac myocyte CL0002131
    CSI 1.36
    rCSI 8.49%
    PRS 71.33
  • pancreatic acinar cell CL0002064
    CSI 1.34
    rCSI 1.78%
    PRS 85.18
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.32
    rCSI 2.33%
    PRS 61.14
  • basal cell of epidermis CL0002187
    CSI 1.24
    rCSI 2.2%
    PRS 49.21
  • cardiac muscle cell CL0000746
    CSI 1.17
    rCSI 1.67%
    PRS 69.64
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1
    rCSI 2.44%
    PRS 59.84
  • suprabasal keratinocyte CL4033013
    CSI 0.93
    rCSI 1.51%
    PRS 46.78
  • pancreatic PP cell CL0002275
    CSI 0.75
    rCSI 2.98%
    PRS 86.87
  • blood vessel smooth muscle cell CL0019018
    CSI 0.36
    rCSI 2.92%
    PRS 73.92

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.

Comma-separated if multiple.
Comma-separated if multiple.
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)

Loading network (please wait)...

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 [NOL3](/details-gene/8996) (Nucleolar Protein 3), also known as ARC (Apoptosis Repressor with CARD), is a protein-coding gene located on chromosome 16q22.1. It is a well-characterized multi-functional protein primarily known for its potent anti-apoptotic activity. [NOL3](/details-gene/8996) functions by directly binding and inhibiting caspases, thereby blocking key steps in both intrinsic and extrinsic cell death pathways [Link](https://doi.org/10.1073/pnas.95.9.5156). In addition to its cytoplasmic role in cell survival, isoforms of [NOL3](/details-gene/8996) localize to the nucleolus and are implicated in RNA splicing [Link](https://doi.org/10.1074/jbc.274.16.10951). **Overall**, expression data indicates its high significance in diverse cell types, including [epithelial cell of lung](/details-cell/CL0000082), [glial cell](/details-cell/CL0000125), and secretory cells, suggesting a broad role in maintaining tissue homeostasis and protecting long-lived cells from stress. Mutations in [NOL3](/details-gene/8996) have been linked to familial cortical myoclonus, highlighting its importance in neurological function [Link](https://doi.org/10.1002/ana.23666). ## Cellular Roles and Expression Landscape The expression profile of [NOL3](/details-gene/8996) suggests its primary role is to support the viability and function of a wide array of specialized, often long-lived cell populations. **Overall**, the gene shows the highest significance in the [epithelial cell of lung](/details-cell/CL0000082) (CSI: 9.23), with substantial expression also noted in other secretory and barrier tissues such as [lung secretory cell](/details-cell/CL1000272) and [intestine goblet cell](/details-cell/CL0019031). This pattern is consistent with its anti-apoptotic function, which may be critical for protecting these high-turnover or environmentally exposed tissues from cellular damage. A second major site of [NOL3](/details-gene/8996) activity is the nervous system and related tissues. It is a significant marker for [glial cell](/details-cell/CL0000125) (CSI: 6.50), [neural progenitor cell](/details-cell/CL0011020) (CSI: 5.56), and [retinal ganglion cell](/details-cell/CL0000740) (CSI: 5.30). This expression pattern aligns with its documented role in neuroprotection and the neurological phenotype observed in patients with [NOL3](/details-gene/8996) mutations [Link](https://doi.org/10.1002/ana.23666). Finally, [NOL3](/details-gene/8996) is also significant in various muscle and stromal cells, including [microcirculation associated smooth muscle cell](/details-cell/CL0008035) and [myofibroblast cell](/details-cell/CL0000186). This is in line with early findings identifying it as an inhibitor of apoptosis in skeletal and cardiac muscle [Link](https://doi.org/10.1073/pnas.95.9.5156) and as a crucial factor for cardioprotection against ischemic stress [Link](https://doi.org/10.1161/circulationaha.105.576785). The absence of major immune cell lineages from the top expressed list suggests a more specialized role in tissue-parenchymal cells rather than in hematopoietic surveillance. ## Pathways and Molecular Function Functional annotations reveal [NOL3](/details-gene/8996) as a central node in the regulation of programmed cell death. Its primary biological process is the **Negative regulation of apoptotic process** ([GO:0043066](https://www.ebi.ac.uk/QuickGO/term/GO:0043066)), which it achieves by inhibiting both the intrinsic ([GO:2001243](https://www.ebi.ac.uk/QuickGO/term/GO:2001243)) and extrinsic ([GO:2001237](https://www.ebi.ac.uk/QuickGO/term/GO:2001237)) signaling pathways. At the molecular level, this is mediated by its **Cysteine-type endopeptidase inhibitor activity involved in apoptotic process** ([GO:0043027](https://www.ebi.ac.uk/QuickGO/term/GO:0043027)). [NOL3](/details-gene/8996) can directly interact with caspases through **Caspase binding** ([GO:0089720](https://www.ebi.ac.uk/QuickGO/term/GO:0089720)) and also engages with **Death receptor binding** ([GO:0005123](https://www.ebi.ac.uk/QuickGO/term/GO:0005123)) to block upstream signals. Its function is further tied to cellular stress responses, including **Response to hypoxia** ([GO:0001666](https://www.ebi.ac.uk/QuickGO/term/GO:0001666)) and **Response to ischemia** ([GO:0002931](https://www.ebi.ac.uk/QuickGO/term/GO:0002931)), consistent with its high expression in metabolically active tissues and its role in cardioprotection [Link](https://doi.org/10.1161/circulationaha.105.576785). Beyond its well-known role in apoptosis, [NOL3](/details-gene/8996) also participates in **Rna splicing** ([GO:0008380](https://www.ebi.ac.uk/QuickGO/term/GO:0008380)) via its **Rna binding** ([GO:0003723](https://www.ebi.ac.uk/QuickGO/term/GO:0003723)) capability. This dual functionality is reflected in its diverse subcellular localization, which includes the **Cytoplasm** ([GO:0005737](https://www.ebi.ac.uk/QuickGO/term/GO:0005737)), **Mitochondrion** ([GO:0005739](https://www.ebi.ac.uk/QuickGO/term/GO:0005739)), and **Nucleolus** ([GO:0005730](https://www.ebi.ac.uk/QuickGO/term/GO:0005730)), allowing it to regulate cell fate from multiple cellular compartments. ## Research Directions The diverse expression pattern and dual functions of [NOL3](/details-gene/8996) in both cell survival and RNA processing present several compelling avenues for future research. **Proposed Hypotheses:** 1. Given that mutations in [NOL3](/details-gene/8996) cause familial cortical myoclonus [Link](https://doi.org/10.1002/ana.23666) and the gene is highly expressed in [glial cell](/details-cell/CL0000125) and [neural progenitor cell](/details-cell/CL0011020), we hypothesize that pathogenic [NOL3](/details-gene/8996) variants impair the homeostatic anti-apoptotic function required for the long-term survival and function of specific glial or neuronal subtypes. This cellular deficit may lead to network instability and the resulting hyperexcitability characteristic of myoclonus. 2. Based on its function as a potent apoptosis inhibitor and its high significance in [epithelial cell of lung](/details-cell/CL0000082), we hypothesize that aberrant overexpression of [NOL3](/details-gene/8996) is a pro-survival mechanism in non-small cell lung cancer, contributing to resistance against apoptosis-inducing chemotherapies. **Experimental Approach:** To test the first hypothesis regarding its neurological role, a key experiment would be to generate a knock-in mouse model harboring a patient-derived mutation using CRISPR-Cas9. This model could then be characterized using a combination of techniques: *in vivo* electroencephalography (EEG) to monitor for seizure or myoclonic activity, single-nucleus RNA sequencing of brain tissue to identify transcriptomic dysregulation in specific cell types like [glial cell](/details-cell/CL0000125), and immunohistochemical analysis to assess cell death markers (e.g., cleaved caspase-3) and neuronal morphology in affected brain regions. **Therapeutic Potential:** [NOL3](/details-gene/8996) presents a dual-natured therapeutic target. On one hand, **inhibition** of [NOL3](/details-gene/8996) could be a viable strategy in oncology. By blocking its anti-apoptotic function, cancer cells—particularly those in lung epithelial tumors where its expression is high—could be re-sensitized to standard chemotherapeutic agents. This approach would be most effective if tumor cells are more dependent on [NOL3](/details-gene/8996) for survival than healthy tissues. On the other hand, **activation** or targeted delivery of [NOL3](/details-gene/8996) protein or mRNA could represent a novel cytoprotective therapy. This strategy holds promise for conditions involving acute ischemic injury, such as myocardial infarction or stroke, where preserving cell viability in the face of stress is paramount.

Genular Protein ID: 2461567808

Symbol: NOL3_HUMAN

Name: N/A

UniProtKB Accession Codes:

O60936 B4DFL0 O60937

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChiTaRS 1 DIP 1 DNASU 1 DisGeNET 1 EMBL 9 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 36 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 RefSeq 8 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9560245

Title: ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases.

PubMed ID: 9560245

DOI: 10.1073/pnas.95.9.5156

PubMed ID: 10196175

Title: Alternative splicing determines the intracellular localization of the novel nuclear protein Nop30 and its interaction with the splicing factor SRp30c.

PubMed ID: 10196175

DOI: 10.1074/jbc.274.16.10951

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15616553

Title: The sequence and analysis of duplication-rich human chromosome 16.

PubMed ID: 15616553

DOI: 10.1038/nature03187

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: 15004034

Title: Apoptosis repressor with caspase recruitment domain protects against cell death by interfering with Bax activation.

PubMed ID: 15004034

DOI: 10.1074/jbc.m400695200

PubMed ID: 15509781

Title: Calcium binding of ARC mediates regulation of caspase 8 and cell death.

PubMed ID: 15509781

DOI: 10.1128/mcb.24.22.9763-9770.2004

PubMed ID: 16505176

Title: Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress.

PubMed ID: 16505176

DOI: 10.1161/circulationaha.105.576785

PubMed ID: 17142452

Title: The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant.

PubMed ID: 17142452

DOI: 10.1074/jbc.m609186200

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 25255805

Title: Global profiling of co- and post-translationally N-myristoylated proteomes in human cells.

PubMed ID: 25255805

DOI: 10.1038/ncomms5919

PubMed ID: 22926851

Title: Familial cortical myoclonus with a mutation in NOL3.

PubMed ID: 22926851

DOI: 10.1002/ana.23666

PubMed ID: 25138476

Title: Screening of mutations in NOL3 in a myoclonic syndromes series.

PubMed ID: 25138476

DOI: 10.1007/s00415-014-7463-z

Sequence Information:

  • Length: 208
  • Mass: 22629
  • Checksum: 239EF1A143EF6168
  • Sequence:
    • MGNAQERPSE TIDRERKRLV ETLQADSGLL LDALLARGVL TGPEYEALDA LPDAERRVRR 
LLLLVQGKGE AACQELLRCA QRTAGAPDPA WDWQHVGPGY RDRSYDPPCP GHWTPEAPGS 
GTTCPGLPRA SDPDEAGGPE GSEAVQSGTP EEPEPELEAE ASKEAEPEPE PEPELEPEAE 
AEPEPELEPE PDPEPEPDFE ERDESEDS