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MUC16 (mucin 16, cell surface associated)

Identity

Other namesCA125
FLJ14303
Mucin-16
HGNC (Hugo) MUC16
LocusID (NCBI) 94025
Location 19p13.2
Location_base_pair Starts at 8959520 and ends at 9092018 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note MUC16 belongs to the subgroup of the membrane-anchored mucin. It is a type-1 glycopotein with heavy O- and N-type glycosylation.

DNA/RNA

 
  Shows the genomic organization of MUC16 gene.
Description In the genome, MUC16 is localized in 19p13.2 chromosome and is coded by sequences present within approximatively 179kb of genomic DNA.
Transcription As per the present available information, there is a discrepancy regarding the total number of exons present in MUC16 genomic DNA. This discrepancy is due to the absence/presence of some of the genomic sequences (particularly for the repeat regions) in the available genomic databases. The terminal nine exons on both 5' and 3' ends code for the amino- and carboxy-terminal domains of MUC16, respectively. At the same time, it has been proposed that five consecutive exons code for a single repeat unit (SRU) of the central tandem repeat domain.

Protein

 
  Shows the structural organization of CA125/MUC16 protein.
Description MUC16 protein harbors a central tandem repeat region, N-terminal domain and carboxy terminal domain. The N-terminal domain has 12070 numbers of amino acids rich in serine/threonine residues and accounts for the major O-glycosylation known to be present in CA125. The MUC16 protein back bone is dominated by tandem repeat region, which has more than 60 repeat domains, each composed of 156 amino acids. Though all the individual repeat units are not similar, most of them occur more than once in the sequence.
The repeat units are rich in serine, threonine and proline residues, which are typical for any mucins. Each repeat unit has some homology to the SEA (Sea-urchin sperm protein, Enterokinase and Agrin) module, whose exact biological function is not known.
The epitopes for known anti-CA125 antibodies (OC125 and M11) are thought to be present on a small cysteine ring region present in the tandem-repeat region of MUC16.
The carboxy-terminal domain has 284 aminoacids and can be divided into three different regions: extra cellular, transmembrane and cytoplasmic tail. The extracellular part of the carboxy-terminal domain has many N-glycosylation sites and some O-glycosyaltion sites. Several in silico analyses suggest a putative cleavage site in the extracellular part of carboxy-terminal domain. The MUC16 cytoplasmic tail is 31 amino acids long and has many possible phosphorylation sites.
The phosphorylation of CA125 in WISH cells has been reported by labeling with 32PO43- and immunoprecipitaion analysis but the exact site of phosphorylation is yet to be mapped. Interestingly, CA125 contains a putative tyrosine phosphorylation site (RRKKEGY), which was first recognized in Src family protein. This sequence is conserved in the translated mouse EST (AK003577) that has homology with CA125/MUC16 at the C-terminal end. Recently, it has been shown that MUC16 cytoplasmic tail, which contains a polybasic aminoacid sequence, interacts with cytoskeleton through ERM (ezrin/radixin/moesin) actin-binding proteins.
Expression The expression of MUC16 has been reported in human epithelia of conjunctiva, cornea, middle ear and trachea under normal physiological conditions. MUC16 is also expressed in ovarian carcinoma.
Localisation It is a type I membrane-bound protein and due to cleavage gets secreted into the extracellular space. On the ocular surface, MUC16 is expressed on the tips of the microplicae of the ocular surface.
Function MUC16 provides a disadhesive protective barrier to the ocular epithelial surface. Overexpression of CA125/MUC16 in ovarian cancer indicates its possible role in cancer pathogenesis. Studies have shown that CA125/MUC16 binds to mesothelin and galectin-1, which are overexpressed in ovarian cancer. It has also been shown that mesothelin-MUC16 interaction has significance in adhesion of ovarian cancer cells to mesothelial cells present on the inner wall of the peritoneum and on the surface of other abdominal organs. This cell to cell adhesion may help in ovarian cancer metastasis. It has been proposed that galectin-1 bound to MUC16 may cause apoptosis of T cells, and thus help in the suppression of the host immunity.
Homology Similar to mucin 16 of Pan troglodytes, Canis lupus familiaris, Mus musculus, Rattus norvegicus and Gallus gallus.

Implicated in

Entity Ovarian cancer
Disease Epithelial ovarian cancer is the most lethal gynaecologic malignancy in the United States and other parts of the world. In the United States, ovarian cancer accounts for approximately 22,000 new cases and 16,000 deaths occurring every year. The epithelial ovarian carcinomas represent approximately 90% of all types of ovarian malignant neoplasms. Due to lack of specific signs and symptoms of this disease, coupled with lack of reliable screening strategies most patients are diagnosed in the advanced stage of the disease, resulting in low overall cure rates. Ovarian cancer patients are generally treated with surgical resection and subsequent platinum-based chemotherapy. Although, many patients initially respond well to chemotherapy, long term survival remains poor due to eventual tumor recurrence and emergence of drug-resistant disease. Overall, the five year survival rate is 45%.
Prognosis Since the last 20 years, CA125/MUC16 has been used as a well-established marker for diagnosis of ovarian cancer. It is mostly overexpressed in serous type of ovarian cancers and less likely to be expressed in mucinous tumors. More than 80% of ovarian cancer patients have elevated CA125 level during their treatment period. It has been shown that the disease progression is associated with an increase in serum CA125 level, while a decline in serum CA125 level is associated with response to therapy. In another finding, it has been shown that the trend of serum CA125 level during the first three courses of chemotherapy is a strong forecaster of re-examination findings in patients with ovarian carcinoma at the end of treatment. Interestingly, it has been shown that a normal CA125 level by the end of second or third chemotherapy is strongly linked to the survival of patients in stage 3 or stage 4 conditions. Also, variations in the CA125 value even within the normal range carry useful information regarding prediction of time to treatment failure. Additionally, in patients in stage 1 cancers it has been suggested that CA125 elevations are not related to the tumor mass volume. Recently, the potential of CA125/MUC16 as a therapeutic target has been harnessed by using an armed human antibody (3A5) against MUC16 protein.
Oncogenesis There is no experimental evidence in the scientific literature for a role of MUC16 in oncogenesis. However, MUC16 possesses many structural similarities with other membrane bound mucins, like MUC1 and MUC4, which are already shown to be functionally involved in different cancers. Transmembrane mucins are hypothesized to serve as sensors of the external environment and can transduce signals via the post-translational modifications of their cytoplasmic tail. Phosphorylation of MUC16 protein has already been reported. Though the exact interacting partner and the site of phosphorylation are unknown, the presence of potential phosphorylation sites in MUC16 cytoplasmic tail indicates the possible role of MUC16 in downstream signal transduction. Further, it has been shown that MUC16 interacts with galectin-1 and mesothelin and these interactions may have a role in cancer progression.
  

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945

External links

Nomenclature
HGNC (Hugo)MUC16   15582
Cards
AtlasMUC16ID41455ch19q13
Entrez_Gene (NCBI)MUC16  94025  mucin 16, cell surface associated
GeneCards (Weizmann)MUC16
Ensembl (Hinxton)ENSG00000181143 [Gene_View]  chr19:8959520-9092018 [Contig_View]  MUC16 [Vega]
ICGC DataPortalENSG00000181143
cBioPortalMUC16
AceView (NCBI)MUC16
Genatlas (Paris)MUC16
WikiGenes94025
SOURCE (Princeton)NM_024690
Genomic and cartography
GoldenPath (UCSC)MUC16  -  19p13.2   chr19:8959520-9092018 -  19p13.2   [Description]    (hg19-Feb_2009)
EnsemblMUC16 - 19p13.2 [CytoView]
Mapping of homologs : NCBIMUC16 [Mapview]
OMIM606154   
Gene and transcription
Genbank (Entrez)AF361486 AF414442 AK024365 AK056791 AK128681
RefSeq transcript (Entrez)NM_024690
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NT_011295 NW_001838482 NW_001838483 NW_004929414
Consensus coding sequences : CCDS (NCBI)MUC16
Cluster EST : UnigeneHs.432676 [ NCBI ]
CGAP (NCI)Hs.432676
Alternative Splicing : Fast-db (Paris)GSHG0033923
Alternative Splicing GalleryENSG00000181143
Gene ExpressionMUC16 [ NCBI-GEO ]     MUC16 [ SEEK ]   MUC16 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8WXI7 (Uniprot)
NextProtQ8WXI7  [Medical]
With graphics : InterProQ8WXI7
Splice isoforms : SwissVarQ8WXI7 (Swissvar)
Domaine pattern : Prosite (Expaxy)SEA (PS50024)   
Domains : Interpro (EBI)MUC16 [organisation]   SEA_dom [organisation]  
Related proteins : CluSTrQ8WXI7
Domain families : Pfam (Sanger)SEA (PF01390)   
Domain families : Pfam (NCBI)pfam01390   
Domain families : Smart (EMBL)SEA (SM00200)  
DMDM Disease mutations94025
Blocks (Seattle)Q8WXI7
Human Protein AtlasENSG00000181143 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ8WXI7
IPIIPI00103552   IPI00876952   IPI01009414   IPI00943307   IPI01015973   IPI01018787   
Protein Interaction databases
DIP (DOE-UCLA)Q8WXI7
IntAct (EBI)Q8WXI7
FunCoupENSG00000181143
BioGRIDMUC16
InParanoidQ8WXI7
Interologous Interaction database Q8WXI7
IntegromeDBMUC16
STRING (EMBL)MUC16
Ontologies - Pathways
Ontology : AmiGOprotein binding  extracellular space  Golgi lumen  plasma membrane  cell adhesion  integral component of membrane  O-glycan processing  extrinsic component of membrane  post-translational protein modification  cellular protein metabolic process  extracellular vesicular exosome  
Ontology : EGO-EBIprotein binding  extracellular space  Golgi lumen  plasma membrane  cell adhesion  integral component of membrane  O-glycan processing  extrinsic component of membrane  post-translational protein modification  cellular protein metabolic process  extracellular vesicular exosome  
Protein Interaction DatabaseMUC16
Wikipedia pathwaysMUC16
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MUC16
snp3D : Map Gene to Disease94025
SNP (GeneSNP Utah)MUC16
SNP : HGBaseMUC16
Genetic variants : HAPMAPMUC16
Exome VariantMUC16
1000_GenomesMUC16 
ICGC programENSG00000181143 
Somatic Mutations in Cancer : COSMICMUC16 
CONAN: Copy Number AnalysisMUC16 
Mutations and Diseases : HGMDMUC16
Genomic VariantsMUC16  MUC16 [DGVbeta]
dbVarMUC16
ClinVarMUC16
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM606154   
MedgenMUC16
GENETestsMUC16
Disease Genetic AssociationMUC16
Huge Navigator MUC16 [HugePedia]  MUC16 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMUC16
Homology/Alignments : Family Browser (UCSC)MUC16
Phylogenetic Trees/Animal Genes : TreeFamMUC16
Chemical/Protein Interactions : CTD94025
Chemical/Pharm GKB GenePA31314
Clinical trialMUC16
Cancer Resource (Charite)ENSG00000181143
Other databases
Probes
Litterature
PubMed152 Pubmed reference(s) in Entrez
CoreMineMUC16
iHOPMUC16
OncoSearchMUC16

Bibliography

The CA 125 gene: an extracellular superstructure dominated by repeat sequences.
O'Brien TJ, Beard JB, Underwood LJ, Dennis RA, Santin AD, York L
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2001 ; 22 (6) : 348-366.
PMID 11786729
 
Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16.
Yin BW, Lloyd KO
The Journal of biological chemistry. 2001 ; 276 (29) : 27371-27375.
PMID 11369781
 
The CA 125 gene: a newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure.
O'Brien TJ, Beard JB, Underwood LJ, Shigemasa K
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2002 ; 23 (3) : 154-169.
PMID 12218296
 
Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene.
Yin BW, Dnistrian A, Lloyd KO
International journal of cancer. Journal international du cancer. 2002 ; 98 (5) : 737-740.
PMID 11920644
 
The cancer antigen CA125 represents a novel counter receptor for galectin-1.
Seelenmeyer C, Wegehingel S, Lechner J, Nickel W
Journal of cell science. 2003 ; 116 (Pt 7) : 1305-1318.
PMID 12615972
 
Solution structure of the SEA domain from the murine homologue of ovarian cancer antigen CA125 (MUC16).
Maeda T, Inoue M, Koshiba S, Yabuki T, Aoki M, Nunokawa E, Seki E, Matsuda T, Motoda Y, Kobayashi A, Hiroyasu F, Shirouzu M, Terada T, Hayami N, Ishizuka Y, Shinya N, Tatsuguchi A, Yoshida M, Hirota H, Matsuo Y, Tani K, Arakawa T, Carninci P, Kawai J, Hayashizaki Y, Kigawa T, Yokoyama S
The Journal of biological chemistry. 2004 ; 279 (13) : 13174-13182.
PMID 14764598
 
Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125).
Chauhan SC, Singh AP, Ruiz F, Johansson SL, Jain M, Smith LM, Moniaux N, Batra SK
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2006 ; 19 (10) : 1386-1394.
PMID 16880776
 
Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 AND MUC16.
Duraisamy S, Ramasamy S, Kharbanda S, Kufe D
Gene. 2006 ; 373 : 28-34.
PMID 16500040
 
Methylation mediated silencing of TMS1/ASC gene in prostate cancer.
Das PM, Ramachandran K, Vanwert J, Ferdinand L, Gopisetty G, Reis IM, Singal R
Molecular cancer. 2006 ; 5 : page 28.
PMID 16848908
 
Functions of MUC16 in corneal epithelial cells.
Blalock TD, Spurr-Michaud SJ, Tisdale AS, Heimer SR, Gilmore MS, Ramesh V, Gipson IK
Investigative ophthalmology & visual science. 2007 ; 48 (10) : 4509-4518.
PMID 17898272
 
Armed antibodies targeting the mucin repeats of the ovarian cancer antigen, MUC16, are highly efficacious in animal tumor models.
Chen Y, Clark S, Wong T, Chen Y, Chen Y, Dennis MS, Luis E, Zhong F, Bheddah S, Koeppen H, Gogineni A, Ross S, Polakis P, Mallet W
Cancer research. 2007 ; 67 (10) : 4924-4932.
PMID 17510422
 
MUC16 is produced in tracheal surface epithelium and submucosal glands and is present in secretions from normal human airway and cultured bronchial epithelial cells.
Davies JR, Kirkham S, Svitacheva N, Thornton DJ, Carlstedt I
The international journal of biochemistry & cell biology. 2007 ; 39 (10) : 1943-1954.
PMID 17604678
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written10-2007Shantibhusan Senapati, Moorthy P Ponnusamy, Ajay P Singh, Maneesh Jain, Surinder K Batra
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Durham Research center 7005, Omaha, NE 68198-5870, USA (SKB)

Citation

This paper should be referenced as such :
Senapati, S ; Ponnusamy, MP ; Singh, AP ; Jain, M ; Batra, SK
MUC16 (mucin 16, cell surface associated)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3):223-225.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/MUC16ID41455ch19q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Jul 30 16:42:02 CEST 2014

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