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MUC5AC (mucin 5AC, oligomeric mucus/gel-forming)

Written2009-07Raquel Mejías-Luque, Lara Cobler, Carme de Bolós
Programa de Recerca en Cancer, IMIM-Hospital del Mar, Dr Aiguader, 88, 08003, Barcelona, Spain

(Note : for Links provided by Atlas : click)

Identity

Alias_namesmucin 5
Alias_symbol (synonym)MUC5
Other aliasLeB
mucin 5AC
TBM
HGNC (Hugo) MUC5AC
LocusID (NCBI) 4586
Atlas_Id 41460
Location 11p15.5  [Link to chromosome band 11p15]
Location_base_pair Starts at 1157953 and ends at 1201141 bp from pter ( according to hg19-Feb_2009)  [Mapping MUC5AC.png]
 
  Location of MUC5AC gene.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

 
  Genomic organization of MUC5AC gene (not to scale).
Description MUC5AC gene approximately extends 150 kb-long on the chromosome 11 in the region p15.5. The central region has sequences repeated in tandem (TR) with a consensus motif composed of 24 bp. The variable number of TR (VNTR) polymorphism is low compared with MUC2 and MUC6. The MUC5AC alleles present small differences in length, but the tandem repeat sequence is highly polymorphic and differs in length by 0.5-1 kb.
Transcription To date, there is a discrepancy regarding the total number of exons present in MUC5AC gene. The full size 5' UTR of MUC5AC has not been yet determined, but it is estimated that the mRNA length is approximately 17.5 kb.
The 4 kb fragment upstream is essential for the cell-specific expression of MUC5AC. It contains a TATA box at -29/-23 and potential transcription factor binding sites are described for NFkappaB, Sp-1, GRE and AP-2. One CACCC box able to bind SP1 and initiate transcription has been identified. At present no splice variant forms have been reported.
The MUC5AC promoter has lower number of CpG dinucleotides compared to the other mucin genes located at 11p15, and no silencing of this gene could be explained by methylation.
Several factors have been shown to induce the transcription of MUC5AC such as cytokines, inflammatory mediators, growth factors, some bacterial exproducts and toxic agents like tobacco smoke and pollutants. Furthermore, it is reported that glucocorticoids downregulate MUC5AC expression.

Protein

Note MUC5AC is a secreted, gel-forming mucin with a high molecular weight (approximately 641 kDa). Up to 80% of the total weight is due to the large number of O-glycosilated chains attached to Thr and Ser residues in the TR sequence.
 
  Schematic representation of MUC5AC peptide structure (not to scale).
Description MUC5AC is a polymeric mucin with a N-terminal region, a central region, and a C-terminal region.
At the N-terminal region, D1, D2, D' and D3 cysteine-rich domains (Cys) similar to von Willebrand factor (vWF) are present, and are responsible for the disulfide-mediated polymer formation. At the central region, coded by a single large exon, nine Cys domains are located: Cys1 to Cys5 are interspersed by domains rich in Ser, Thr and Pro (STP) with no repetitive sequences, whereas Cys5 to Cys9 domains are interspersed by four TR domains. The consensus repetitive sequence most frequent is TTSTTSAP containing a high number of potential O-glycosilation sites. The C-terminal region has the cysteine-rich vWF-like domains D4, B, C and CK. The CK domain mediates the formation of disulfide-linked dimmers by an autocatalytic process. Towards the C-terminus, contains an autocatalytic protein-cleavage site at the motif GDPH.
Expression MUC5AC was initially isolated from a human tracheobronchial cDNA library, and it is highly expressed in the goblet cells of the respiratory epithelium. MUC5AC is also highly detected in the superficial gastric epithelium, and it is also expressed in pancreas, endocervix and gallbladder.
Under pathological conditions, MUC5AC expression can be altered, as it is reported below. The changes associated with neoplastic transformation and inflammatory diseases, can be induced by the activation of signaling pathways in response to several factors such as inflammatory cytokines, growth factors, and bacterial products.
Function MUC5AC is a gel-forming mucin and it is a major constituent of the mucus lining mainly the respiratory tract and the stomach. In the surface of the normal respiratory epithelium, MUC5AC is one of the major contributors to the rheological properties of the mucus that has a critical role in the defense against pathogenic and environmental challenges. In the gastric mucosa, MUC5AC and MUC6 are the main components of the protective layer over the surface, and act as a selective diffusion barrier for HCl. MUC5AC also protect the gastric epithelium from Helicobacter pylori, and the glycan structures on MUC5AC, Leb and sialyl Lex, act as ligands for the bacterium competing with the ligands located on the epithelial cell surface.
Homology Several orthologues of MUC5AC have been identified in Mus musculus, Rattus norvegicus, Canis lupus familiaris, Equus caballus and Pan troglodytes. The chicken, horse and mouse Muc5AC have a similar domain structure. Murine N-terminal and C-terminal regions showed striking similarities with human MUC5AC, whereas the TSP domains are specific for species. Furthermore, MUC5AC tissue-specific expression is conserved in murine and equine organisms.

Implicated in

Note
  
Entity Gastric cancer
Disease Gastric cancer remains the second leading cause of cancer related deaths and the fourth most common cancer in the world, although its incidence is gradually decreasing.
Prognosis Gastric neoplastic transformation is associated with a decreased expression of MUC5AC. MUC5AC is used as a marker of gastric phenotype in stomach tumours, and its expression is associated with antral carcinomas. MUC5AC expression have been also related to tumour stage: it is expressed in early carcinomas while advanced gastric cancers present reduced levels of MUC5AC.
  
  
Entity Colon cancer
Disease Colorectal cancer is one of the commonest cancers and the third leading cause of cancer death. However, its incidence has decreased due to a most effective intervention and life-style changes in the western countries.
Prognosis MUC5AC has been detected in precancerous lesions as well as in colon cancer, and this ectopic expression may represent a nonspecific repair function of the colon cells to compensate for damage to barrier function.
  
  
Entity Endometrial adenocarcinoma
Disease Endometrial adenocarcinoma is the most common malignant neoplasm of the female genital tract in developed countries, and it occurs predominantly after menopause.
Prognosis Increased levels of MUC5AC have been found in endometrial adenocarcinoma compared to normal endometrium and endometrial hyperplasia, suggesting a potential role for MUC5AC as a marker of endometrial neoplastic transformation.
  
  
Entity Pancreatic cancer
Disease Pancreas cancer is a very aggressive tumor with a 5-year survival of less than 5%, and approximately 85% of them correspond to ductal adenocarcinomas.
Prognosis The ectopic expression of MUC5AC in pancreas ductal adenocarcinomas is an early event, already detected in the PanIN1A (pancreatic intraepithelial neoplasia 1A) stage. The MUC5AC expression is maintained to reach 85% of the pancreatic tumors.
  
  
Entity Biliary tract cancer
Disease Biliary tract carcinomas are uncommon tumors that includes cholangiocarcinomas and gallbladder carcinomas. These tumors has a poor prognosis: more than 80% of the patients are unresectable with a 6-9 month survival, and this rate is increased to 5-year after surgery.
Prognosis MUC5AC is detected at very low levels in biliary tract carcinomas and its expression do not correlate with the clinical stage of the tumor. However, the detection of MUC5AC in sera from biliary tract carcinoma patients, associated to the MUC4 expression in the tumor, have been suggested as a highly specific markers for this neoplasia.
  
  
Entity Airways pathologies: asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and nasal polyps (NP) in upper airways
Disease Asthma has grown, particularly among children, in prevalence and it is characterized by an airflow obstruction caused by inflammation-induced changes in airway smooth muscle contraction and by mucus hypersecretion.
CF is characterized by impaired mucociliary clearance, leading to chronic airflow obstruction and to recurrent infections.
COPD is the fourth leading cause of death in the U.S. and Europe. Submucosal gland hypertrophy and airway surface metaplasia are the hallmarks of COPD.
NP is an inflammatory disease whose aetiology is still unknown and affects 2-4% of general population.
Prognosis MUC5AC levels have been found to be increased in asthma, CF and COPD that alter the transport properties of the mucus gel and provide a favourable environment for pathogens. In NP a decrease of MUC5AC levels are detected.
  

Bibliography

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Gastric M1 mucin, an early oncofetal marker of colon carcinogenesis, is encoded by the MUC5AC gene.
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The mouse secreted gel-forming mucin gene cluster.
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An inventory of mucin genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part of a locus of related gel-forming mucins.
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Cloning of the amino-terminal and 5'-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts.
Li D, Gallup M, Fan N, Szymkowski DE, Basbaum CB.
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PMID 9506983
 
Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns.
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Corticosteroid therapy increases membrane-tethered while decreases secreted mucin expression in nasal polyps.
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Citation

This paper should be referenced as such :
Mejias-Luque, R ; Cobler, L ; de, Bolòs C
MUC5AC (mucin 5AC, oligomeric mucus/gel-forming)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(6):566-569.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MUC5ACID41460ch11p15.html


External links

,TD>158373   
Nomenclature
HGNC (Hugo)MUC5AC   7515
Cards
AtlasMUC5ACID41460ch11p15
Entrez_Gene (NCBI)MUC5AC  4586  mucin 5AC, oligomeric mucus/gel-forming
AliasesMUC5; TBM; leB; mucin
GeneCards (Weizmann)MUC5AC
Ensembl hg19 (Hinxton)ENSG00000215182 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000215182 [Gene_View]  chr11:1157953-1201141 [Contig_View]  MUC5AC [Vega]
ICGC DataPortalENSG00000215182
TCGA cBioPortalMUC5AC
AceView (NCBI)MUC5AC
Genatlas (Paris)MUC5AC
WikiGenes4586
SOURCE (Princeton)MUC5AC
Genetics Home Reference (NIH)MUC5AC
Genomic and cartography
GoldenPath hg38 (UCSC)MUC5AC  -     chr11:1157953-1201141 +  11p15.5   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MUC5AC  -     11p15.5   [Description]    (hg19-Feb_2009)
EnsemblMUC5AC - 11p15.5 [CytoView hg19]  MUC5AC - 11p15.5 [CytoView hg38]
Mapping of homologs : NCBIMUC5AC [Mapview hg19]  MUC5AC [Mapview hg38]
OMIM
Gene and transcription
Genbank (Entrez)AF015521 AF043909 AJ001402 AJ292079 AJ298317
RefSeq transcript (Entrez)NM_001304359 NM_017511
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MUC5AC
Cluster EST : UnigeneHs.721515 [ NCBI ]
CGAP (NCI)Hs.721515
Alternative Splicing GalleryENSG00000215182
Gene ExpressionMUC5AC [ NCBI-GEO ]   MUC5AC [ EBI - ARRAY_EXPRESS ]   MUC5AC [ SEEK ]   MUC5AC [ MEM ]
Gene Expression Viewer (FireBrowse)MUC5AC [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4586
GTEX Portal (Tissue expression)MUC5AC
Human Protein AtlasENSG00000215182-MUC5AC [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP98088   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP98088  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP98088
Splice isoforms : SwissVarP98088
PhosPhoSitePlusP98088
Domaine pattern : Prosite (Expaxy)CTCK_1 (PS01185)    CTCK_2 (PS01225)    VWFC_1 (PS01208)    VWFC_2 (PS50184)    VWFD (PS51233)   
Domains : Interpro (EBI)Cys_knot_C    MUC2    TIL_dom    Unchr_dom_Cys-rich    VWF_dom    VWF_type-D    WxxW_domain   
Domain families : Pfam (Sanger)C8 (PF08742)    Mucin2_WxxW (PF13330)    TIL (PF01826)    VWD (PF00094)   
Domain families : Pfam (NCBI)pfam08742    pfam13330    pfam01826    pfam00094   
Domain families : Smart (EMBL)C8 (SM00832)  CT (SM00041)  VWC (SM00214)  VWC_out (SM00215)  VWD (SM00216)  
Conserved Domain (NCBI)MUC5AC
DMDM Disease mutations4586
Blocks (Seattle)MUC5AC
PDB (SRS)5AJN    5AJO    5AJP   
PDB (PDBSum)5AJN    5AJO    5AJP   
PDB (IMB)5AJN    5AJO    5AJP   
PDB (RSDB)5AJN    5AJO    5AJP   
Structural Biology KnowledgeBase5AJN    5AJO    5AJP   
SCOP (Structural Classification of Proteins)5AJN    5AJO    5AJP   
CATH (Classification of proteins structures)5AJN    5AJO    5AJP   
SuperfamilyP98088
Human Protein Atlas [tissue]ENSG00000215182-MUC5AC [tissue]
Peptide AtlasP98088
IPIIPI00103397   IPI00784209   IPI00383270   IPI01018897   
Protein Interaction databases
DIP (DOE-UCLA)P98088
IntAct (EBI)P98088
FunCoupENSG00000215182
BioGRIDMUC5AC
STRING (EMBL)MUC5AC
ZODIACMUC5AC
Ontologies - Pathways
QuickGOP98088
Ontology : AmiGOstimulatory C-type lectin receptor signaling pathway  extracellular matrix structural constituent  extracellular space  cytoplasm  Golgi lumen  plasma membrane  O-glycan processing  phosphatidylinositol-mediated signaling  extracellular exosome  mucus layer  
Ontology : EGO-EBIstimulatory C-type lectin receptor signaling pathway  extracellular matrix structural constituent  extracellular space  cytoplasm  Golgi lumen  plasma membrane  O-glycan processing  phosphatidylinositol-mediated signaling  extracellular exosome  mucus layer  
NDEx NetworkMUC5AC
Atlas of Cancer Signalling NetworkMUC5AC
Wikipedia pathwaysMUC5AC
Orthology - Evolution
OrthoDB4586
GeneTree (enSembl)ENSG00000215182
Phylogenetic Trees/Animal Genes : TreeFamMUC5AC
HOVERGENP98088
HOGENOMP98088
Homologs : HomoloGeneMUC5AC
Homology/Alignments : Family Browser (UCSC)MUC5AC
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMUC5AC [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MUC5AC
dbVarMUC5AC
ClinVarMUC5AC
1000_GenomesMUC5AC 
Exome Variant ServerMUC5AC
ExAC (Exome Aggregation Consortium)ENSG00000215182
GNOMAD BrowserENSG00000215182
Genetic variants : HAPMAP4586
Genomic Variants (DGV)MUC5AC [DGVbeta]
DECIPHERMUC5AC [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMUC5AC 
Mutations
ICGC Data PortalMUC5AC 
TCGA Data PortalMUC5AC 
Broad Tumor PortalMUC5AC
OASIS PortalMUC5AC [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMUC5AC  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMUC5AC
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MUC5AC
DgiDB (Drug Gene Interaction Database)MUC5AC
DoCM (Curated mutations)MUC5AC (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MUC5AC (select a term)
intoGenMUC5AC
NCG5 (London)MUC5AC
Cancer3DMUC5AC(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM158373   
Orphanet
MedgenMUC5AC
Genetic Testing Registry MUC5AC
NextProtP98088 [Medical]
TSGene4586
GENETestsMUC5AC
Target ValidationMUC5AC
Huge Navigator MUC5AC [HugePedia]
snp3D : Map Gene to Disease4586
BioCentury BCIQMUC5AC
ClinGenMUC5AC
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4586
Chemical/Pharm GKB GenePA31320
Clinical trialMUC5AC
Miscellaneous
canSAR (ICR)MUC5AC (select the gene name)
Probes
Litterature
PubMed264 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMUC5AC
EVEXMUC5AC
GoPubMedMUC5AC
iHOPMUC5AC
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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