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

2009-07-01   Raquel Mejías-Luque , Lara Cobler , Carme de Bolós 

Programa de Recerca en Cancer, IMIM-Hospital del Mar, Dr Aiguader, 88, 08003, Barcelona, Spain

Identity

HGNC
LOCATION
11p15.5
IMAGE
Atlas Image
LEGEND
Location of MUC5AC gene.
LOCUSID
ALIAS
MUC5,TBM,leB,mucin

DNA/RNA

Atlas Image
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.

Proteins

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.
Atlas Image
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

Entity name
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 name
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 name
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 name
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 name
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 name
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.
NP is an inflammatory disease whose aetiology is still unknown and affects 2-4% of general population. 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.
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

Pubmed IDLast YearTitleAuthors
171978982007Mucin genes (MUC2, MUC4, MUC5AC, and MUC6) detection in normal and pathological endometrial tissues.Alameda F et al
164876612006Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases.Andrianifahanana M et al
169356842006Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys.Asher MI et al
94952471998Gastric M1 mucin, an early oncofetal marker of colon carcinogenesis, is encoded by the MUC5AC gene.Bara J et al
14481681992Viscous fingering of HCl through gastric mucin.Bhaskar KR et al
115351372001Human mucin gene MUC5AC: organization of its 5'-region and central repetitive region.Escande F et al
149849302004The mouse secreted gel-forming mucin gene cluster.Escande F et al
175657372007Abnormal expression of M1/MUC5AC mucin in distal colon of patients with diverticulitis, ulcerative colitis and cancer.Forgue-Lafitte ME et al
78263321995Characterization of the human mucin gene MUC5AC: a consensus cysteine-rich domain for 11p15 mucin genes?Guyonnet Duperat V et al
123604672002Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas.Kim GE et al
168870382006An 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.Lang T et al
95069831998Cloning of the amino-terminal and 5'-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts.Li D et al
111526462001Mucins as differentiation markers in bronchial epithelium. Squamous cell carcinoma and adenocarcinoma display similar expression patterns.López-Ferrer A et al
123543382002Chronic obstructive pulmonary disease surveillance--United States, 1971-2000.Mannino DM et al
185472872008Corticosteroid therapy increases membrane-tethered while decreases secreted mucin expression in nasal polyps.Martínez-Antón A et al
184753012008MUC4 and MUC5AC are highly specific tumour-associated mucins in biliary tract cancer.Matull WR et al
120771472002Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1.Perrais M et al
89757111996Human mucin genes assigned to 11p15.5: identification and organization of a cluster of genes.Pigny P et al
172933732007Muc5b and Muc5ac are the major oligomeric mucins in equine airway mucus.Rousseau K et al
178502132008Structure and function of the polymeric mucins in airways mucus.Thornton DJ et al
95448521998Variable number tandem repeat polymorphism of the mucin genes located in the complex on 11p15.5.Vinall LE et al
164561832006Regulation of mucin genes in chronic inflammatory airway diseases.Voynow JA et al
115789532001Regulation of mucin and glycoconjugate expression: from normal epithelium to gastric tumors.de Bolos C et al

Other Information

Locus ID:

NCBI: 4586
MIM: 158373
HGNC: 7515
Ensembl: ENSG00000215182

Variants:

dbSNP: 4586
ClinVar: 4586
TCGA: ENSG00000215182
COSMIC: MUC5AC

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000215182ENST00000621226P98088

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
O-linked glycosylationREACTOMER-HSA-5173105
O-linked glycosylation of mucinsREACTOMER-HSA-913709
Termination of O-glycan biosynthesisREACTOMER-HSA-977068
DiseaseREACTOMER-HSA-1643685
Diseases of glycosylationREACTOMER-HSA-3781865
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
Dectin-2 familyREACTOMER-HSA-5621480
Diseases associated with O-glycosylation of proteinsREACTOMER-HSA-3906995
Defective C1GALT1C1 causes Tn polyagglutination syndrome (TNPS)REACTOMER-HSA-5083632
Defective GALNT3 causes familial hyperphosphatemic tumoral calcinosis (HFTC)REACTOMER-HSA-5083625
Defective GALNT12 causes colorectal cancer 1 (CRCS1)REACTOMER-HSA-5083636
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
215023302011Muc5ac: a critical component mediating the rejection of enteric nematodes.109
177034122007Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.100
156403472005Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells.83
198411862009Regulation of airway MUC5AC expression by IL-1beta and IL-17A; the NF-kappaB paradigm.73
235270032013The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium.71
123604672002Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas.70
161481492005Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme.62
126901132003Interleukin-1 beta and tumor necrosis factor-alpha induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells.61
119190812002Neutrophil elastase induces MUC5AC gene expression in airway epithelium via a pathway involving reactive oxygen species.58
189783022009Rhinovirus-induced major airway mucin production involves a novel TLR3-EGFR-dependent pathway.52

Citation

Raquel Mejías-Luque ; Lara Cobler ; Carme de Bolós

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

Atlas Genet Cytogenet Oncol Haematol. 2009-07-01

Online version: http://atlasgeneticsoncology.org/gene/41460/muc5ac