Mucin short variant S1

Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the MUC1 gene in humans.^[3] Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs.^[4] Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface.^[5] Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers.^[6] Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors.

MUC1
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 1SM3, 2ACM
Identifiers
Aliases	MUC1, ADMCKD, ADMCKD1, CA 15-3, CD227, EMA, H23AG, KL-6, MAM6, MCD, MCKD, MCKD1, MUC-1, MUC-1/SEC, MUC-1/X, MUC1/ZD, PEM, PEMT, PUM, mucin 1, cell surface associated, ADTKD2, Ca15-3, Mucin-1
External IDs	OMIM: 158340; HomoloGene: 136477; GeneCards: MUC1; OMA:MUC1 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q22 Start 155,185,824 bp[1] End 155,192,916 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pylorus pancreatic ductal cell nasal epithelium right uterine tube cardia olfactory zone of nasal mucosa lower lobe of lung buccal mucosa cell gastric mucosa palpebral conjunctiva n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding transcription coregulator activity RNA polymerase II cis-regulatory region sequence-specific DNA binding p53 binding Cellular component extracellular region cytoplasm integral component of membrane nucleus Golgi lumen integral component of plasma membrane apical plasma membrane membrane vesicle extracellular exosome extracellular space plasma membrane Biological process positive regulation of histone H4 acetylation regulation of transcription from RNA polymerase II promoter in response to stress DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator negative regulation of cell adhesion mediated by integrin DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator positive regulation of transcription from RNA polymerase II promoter in response to stress O-glycan processing negative regulation of transcription by competitive promoter binding stimulatory C-type lectin receptor signaling pathway cytokine-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4582 n/a Ensembl ENSG00000185499 n/a UniProt P15941 Q7Z551 n/a RefSeq (mRNA) NM_001018016 NM_001018017 NM_001018021 NM_001044390 NM_001044391 NM_001044392 NM_001044393 NM_001204285 NM_001204286 NM_001204287 NM_001204288 NM_001204289 NM_001204290 NM_001204291 NM_001204292 NM_001204293 NM_001204294 NM_001204295 NM_001204296 NM_001204297 NM_002456 NM_182741 NM_001371720 n/a RefSeq (protein) NP_001018016 NP_001018017 NP_001037855 NP_001037856 NP_001037857 NP_001037858 NP_001191214 NP_001191215 NP_001191216 NP_001191217 NP_001191218 NP_001191219 NP_001191220 NP_001191221 NP_001191222 NP_001191223 NP_001191224 NP_001191225 NP_001191226 NP_002447 NP_001358649 NP_001191217.1 NP_001191225.1 NP_001037856.1 n/a Location (UCSC) Chr 1: 155.19 – 155.19 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

Structure

MUC1 is a member of the mucin family and encodes a membrane bound, glycosylated phosphoprotein. MUC1 has a core protein mass of 120-225 kDa which increases to 250-500 kDa with glycosylation. It extends 200-500 nm beyond the surface of the cell.^[7]

The protein is anchored to the apical surface of many epithelia by a transmembrane domain. Beyond the transmembrane domain is a SEA domain that contains a cleavage site for release of the large extracellular domain. The release of mucins is performed by sheddases.^[8] The extracellular domain includes a 20 amino acid variable number tandem repeat (VNTR) domain, with the number of repeats varying from 20 to 120 in different individuals. These repeats are rich in serine, threonine and proline residues which permits heavy o-glycosylation.^[7]

Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length nature of only some has been determined.^[9]

MUC1 is cleaved in the endoplasmic reticulum into two pieces, the cytoplasmic tail including the transmembrane domain and the extracellular domain. These domains tightly associate in a non-covalent fashion.^[10] This tight, non-covalent association is not broken by treatment with urea, low pH, high salt or boiling. Treatment with sodium dodecyl sulfate triggers dissociation of the subunits.^[11] The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosphorylation sites.^[12]

Function

The protein serves a protective function by binding to pathogens^[13] and also functions in a cell signaling capacity.^[12]

Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. e.g. The CanAg tumour antigen is a novel glycoform of MUC1.^[14] In the cell nucleus, the protein MUC1 regulates the activity of transcription factor complexes that have a documented role in tumor-induced changes of host immunity.^[15]

Interactions

MUC1 has been shown to interact with:

• CTNND1,^[16]
• ERBB2,^[17][18]
• GRB2,^[19]
• JUP,^[17] and
• SOS1.^[18][19]

Role in cancer

The ability of chemotherapeutic drugs to access the cancer cells is inhibited by the heavy glycosylation in the extracellular domain of MUC1. The glycosylation creates a highly hydrophilic region which prevents hydrophobic chemotherapeutic drugs from passing through. This prevents the drugs from reaching their targets which usually reside within the cell. Similarly, the glycosylation has been shown to bind to growth factors. This allows cancer cells which produce a large amount of MUC1 to concentrate growth factors near their receptors, increasing receptor activity and the growth of cancer cells. MUC1 also prevents the interaction of immune cells with receptors on the cancer cell surface through steric hindrance. This inhibits an anti-tumor immune response.^[4]

Preventing cell death

MUC1 cytoplasmic tail has been shown to bind to p53. This interaction is increased by genotoxic stress. MUC1 and p53 were found to be associated with the p53 response element of the p21 gene promoter. This results in activation of p21 which results in cell cycle arrest. Association of MUC1 with p53 in cancer results in inhibition of p53-mediated apoptosis and promotion of p53-mediated cell cycle arrest.^[20]

Overexpression of MUC1 in fibroblasts increased the phosphorylation of Akt. Phosphorylation of Akt results in phosphorylation of Bcl-2-associated death promoter. This results in dissociation of Bcl-2-associated death promoter with Bcl-2 and Bcl-xL. Activation was shown to be dependent on the upstream activation of PI3K. Additionally, MUC1 was shown to increase expression of Bcl-xL. Overexpression of MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents the release of cytochrome c from mitochondria, thereby preventing apoptosis.^[21] MUC1 cytoplasmic tail is shuttled to the mitochondria through interaction with hsp90. This interaction is induced through phosphorylation of the MUC1 cytoplasmic tail by Src (gene). Src is activated by the EGF receptor family ligand Neuregulin. The cytoplasmic tail is then inserted into the mitochondrial outer membrane. Localization of MUC1 to the mitochondria prevents the activation of apoptotic mechanisms.^[22]

Promoting tumor invasion

MUC1 cytoplasmic tail was shown to interact with Beta-catenin. A SXXXXXSSL motif was identified in MUC1 that is conserved with other beta-catenin binding partners. This interaction was shown to be dependent on cell adhesion.^[23] Studies have demonstrated that MUC1 is phosphorylated on a YEKV motif. Phosphorylation of this site has been demonstrated by LYN through mediation of interleukin 7,^[24] Src through mediation of EGFR,^[25][26] and PRKCD.^[27] This interaction is antagonized by degradation of beta-catenin by GSK3B. MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B.^[28][29] The result is that increased expression of MUC1 in cancer increases stabilized beta-catenin. This promotes the expression of vimentin and CDH2. These proteins are associated with a mesenchymal phenotype, characterized by increased motility and invasiveness. In cancer cells, increased expression of MUC1 promotes cancer cell invasion through beta-catenin, resulting in the initiation of epithelial-mesenchymal transition which promotes the formation of metastases.^[30][31]

Diagnostic uses

Blood tests: Cancer Antigens (CA) 27.29 and 15-3

CA 27.29 (aka BR 27.29) and CA 15-3 measure different epitopes of the same protein antigen product of the MUC1 gene seen in breast cancer. CA 27.29 has enhanced sensitivity and specificity compared to CA 15-3 and is elevated in 30% of patients with low-stage disease and 60 to 70% of patients with advanced-stage breast cancer.

CA 27.29 levels over 100 U/mL and CA 15-3 levels over 25 U/mL are rare in benign conditions and suggest malignancy.

Immunohistochemistry

Using immunohistochemistry, MUC1 can be identified in a wide range of secretory epithelia and their neoplastic equivalents:^[32]

• It is a marker of various types of cancer (see below).^[32]
• In micropapillary carcinoma of the breast and bladder, MUC1 stains the stroma-facing surface of cell clusters of micropapillary units.^[32]
• It can distinguish systemic anaplastic large cell lymphoma (MUC1 positive) from cutaneous anaplastic large cell lymphoma (usually MUC1 negative).^[32]
• Although other antibodies, such as cytokeratins, are more commonly used for the identification of metastatic carcinoma deposits, EMA can be used to distinguish mesothelioma, in which it is restricted to the cell membranes and associated micovilli, from adenocarcinoma, in which it is diffusely spread through the cytoplasm.^[33]

Diseases with positive MUC1 staining [32] Adenocarcinomas Breast cancer Colorectal cancer Pancreatic cancer Carcinoid tumor, chordoma Choriocarcinoma Desmoplastic small-round-cell tumor Epithelioid sarcoma Follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, reticulum cell sarcoma Lung: Type II cell lesions (hyperplasia, dysplasia) Lymphomas Anaplastic large-cell lymphoma Diffuse large B-cell lymphoma (variable expression) Plasmablastic lymphoma Primary effusion lymphoma Meningioma Mesotheliomas (epithelioid) Myeloma Paget's disease of the breast Perineurioma Plasmacytomas Renal cell carcinoma Synovial sarcoma (epithelial areas) Thymic carcinoma (often)

Negative staining [32] Myoepithelial cells Adrenocortical carcinoma Hepatocellular carcinoma Germ cell tumors (except choriocarcinoma) Acquired cystic kidney disease-associated renal cell carcinoma Leiomyosarcoma (usually) Liposarcoma Melanoma Neuroblastoma Paraganglioma Solitary fibrous tumor Normal tissues with positive staining [32] Apical surface of almost all glandular and ductal epithelial cells: Breast, including Toker cells Distal convoluted tubule of kidney Type II cells of pulmonary alveoli Pancreas Salivary glands eccrine and apocrine glands of the skin Several white blood cells: Activated T cells Some B cells Monocytes Follicular dendritic cells Perineurial cells

As a therapeutic drug target

Using MUC1, vaccines are being tested against a type of blood cancer called multiple myeloma. The technology could in theory be applied to 90 percent of all known cancers, including prostate and breast cancer, solid and non-solid tumors. This method would activate the immune system by training T-cells to search out and destroy cells that display a specific molecule (or marker) of MUC1. MUC1 is found on nearly all epithelial cells, but it is over expressed in cancer cells, and its associated glycans are shorter than those of non-tumor-associated MUC1.^[34]

Because MUC1 is overexpressed (and differently glycosylated) in many cancers it has been investigated as a drug target, e.g. for the MUC1 vaccine ONT-10, which has had a phase 1 clinical study.^[35]

See also

• Cluster of differentiation
• List of histologic stains that aid in diagnosis of cutaneous conditions
• Mucin-1

References

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11. Julian J, Carson DD (May 2002). "Formation of MUC1 metabolic complex is conserved in tumor-derived and normal epithelial cells". Biochem Biophys Res Commun. 293 (4): 1183–1190. doi:10.1016/S0006-291X(02)00352-2. PMID 12054500.
12. Singh PK, Hollingsworth MA (August 2006). "Cell surface-associated mucins in signal transduction". Trends Cell Biol. 16 (9): 467–476. doi:10.1016/j.tcb.2006.07.006. PMID 16904320.
13. Lindén SK, Sheng YH, Every AL, Miles KM, Skoog EC, Florin TH, Sutton P, McGuckin MA (October 2009). "MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy". PLOS Pathog. 5 (10): e1000617. doi:10.1371/journal.ppat.1000617. PMC 2752161. PMID 19816567.
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15. Vlahopoulos, SA (15 August 2017). "Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode". Cancer Biology & Medicine. 14 (3): 254–270. doi:10.20892/j.issn.2095-3941.2017.0029. PMC 5570602. PMID 28884042.
16. Li Y, Kufe D (February 2001). "The Human DF3/MUC1 carcinoma-associated antigen signals nuclear localization of the catenin p120(ctn)". Biochem. Biophys. Res. Commun. 281 (2): 440–3. doi:10.1006/bbrc.2001.4383. PMID 11181067.
17. Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D (August 2003). "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein". Mol. Cancer Res. 1 (10): 765–75. PMID 12939402.
18. Schroeder JA, Thompson MC, Gardner MM, Gendler SJ (April 2001). "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland". J. Biol. Chem. 276 (16): 13057–64. doi:10.1074/jbc.M011248200. PMID 11278868.
19. Pandey P, Kharbanda S, Kufe D (September 1995). "Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein". Cancer Res. 55 (18): 4000–4003. PMID 7664271.
20. Wei X, Xu H, Kufe D (February 2005). "Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response". Cancer Cell. 7 (2): 167–178. doi:10.1016/j.ccr.2005.01.008. PMID 15710329.
21. Raina D, Kharbanda S, Kufe D (May 2004). "The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts". J Biol Chem. 279 (20): 20607–20612. doi:10.1074/jbc.M310538200. PMID 14999001.
22. Ren J, Bharti A, Raina D, Chen W, Ahmad R, Kufe D (January 2006). "MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90". Oncogene. 25 (1): 20–31. doi:10.1038/sj.onc.1209012. PMID 16158055.
23. Yamamoto M, Bharti A, Li Y, Kufe D (May 1997). "Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion". J. Biol. Chem. 272 (19): 12492–4. doi:10.1074/jbc.272.19.12492. PMID 9139698.
24. Li Y, Chen W, Ren J, Yu WH, Li Q, Yoshida K, Kufe D (2003). "DF3/MUC1 signaling in multiple myeloma cells is regulated by interleukin-7". Cancer Biol. Ther. 2 (2): 187–93. doi:10.4161/cbt.2.2.282. PMID 12750561.
25. Li Y, Kuwahara H, Ren J, Wen G, Kufe D (March 2001). "The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin". J. Biol. Chem. 276 (9): 6061–4. doi:10.1074/jbc.C000754200. PMID 11152665.
26. Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL, Kufe D (September 2001). "The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin". J. Biol. Chem. 276 (38): 35239–42. doi:10.1074/jbc.C100359200. PMID 11483589.
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31. Roy LD, Sahraei M, Subramani DB, Besmer D, Nath S, Tinder TL, Bajaj E, Shanmugam K, Lee YY, Hwang SI, Gendler SJ, Mukherjee P (March 2011). "MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition". Oncogene. 30 (12): 1449–1459. doi:10.1038/onc.2010.526. PMC 3063863. PMID 21102519.
32. Nat Pernick. "Stains - Epithelial membrane antigen (EMA)". PathologyOutlines. Topic Completed: 1 May 2012. Revised: 18 September 2019
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35. Nemunaitis J, Bedell C, Klucher K, Vo A, Whiting S (2013). "Phase 1 dose escalation of ONT-10, a therapeutic MUC1 vaccine, in patients with advanced cancer". Journal for Immunotherapy of Cancer. 1 (Suppl 1): P240. doi:10.1186/2051-1426-1-S1-P240. ISSN 2051-1426. PMC 3990302.

Further reading

• Peterson JA, Scallan CD, Ceriani RL, Hamosh M (2002). "Structural and Functional Aspects of Three Major Glycoproteins of the Human Milk Fat Globule Membrane". Bioactive Components of Human Milk. Advances in Experimental Medicine and Biology. Vol. 501. pp. 179–87. doi:10.1007/978-1-4615-1371-1_23. ISBN 978-1-4613-5521-2. PMID 11787681.
• Hu XF, Yang E, Li J, Xing PX (2006). "MUC1 cytoplasmic tail: a potential therapeutic target for ovarian carcinoma". Expert Rev Anticancer Ther. 6 (8): 1261–71. doi:10.1586/14737140.6.8.1261. PMID 16925492. S2CID 36159399.
• Leroy X, Buisine MP, Leteurtre E, et al. (2007). "[MUC1 (EMA): A key molecule of carcinogenesis?]". Annales de Pathologie. 26 (4): 257–66. doi:10.1016/S0242-6498(06)70718-0. PMID 17128152.
• Li Y, Cozzi PJ (2007). "MUC1 is a promising therapeutic target for prostate cancer therapy". Current Cancer Drug Targets. 7 (3): 259–71. doi:10.2174/156800907780618338. PMID 17504123.
• Mahanta S, Fessler SP, Park J, Bamdad C (April 2008). "A minimal fragment of MUC1 mediates growth of cancer cells". PLOS ONE. 3 (4): e2054. Bibcode:2008PLoSO...3.2054M. doi:10.1371/journal.pone.0002054. PMC 2329594. PMID 18446242.
• Hikita ST, Kosik KS, Clegg DO, Bamdad C (October 2008). "MUC1* mediates the growth of human pluripotent stem cells". PLOS ONE. 3 (10): e3312. Bibcode:2008PLoSO...3.3312H. doi:10.1371/journal.pone.0003312. PMC 2553196. PMID 18833326.
• Fessler SP, Wotkowicz MT, Mahanta S, Bamdad C (2009). "MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells". Breast Cancer Res Treat. 118 (1): 113–24. doi:10.1007/s10549-009-0412-3. PMID 19415485. S2CID 25176184.
• Zhan XX, Zhao B, Diao C, Cao Y, Cheng RC (2015). "Expression of MUC1 and CD176 (Thomsen-Friedenreich antigen) in papillary thyroid carcinomas". Endocr. Pathol. 26 (1): 21–6. doi:10.1007/s12022-015-9356-9. PMID 25614211. S2CID 37471701.

External links

• MUC1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.