Trends in Molecular Medicine
ReviewMUC1: a multifaceted oncoprotein with a key role in cancer progression
Section snippets
Mucin 1: a membrane tethered glycoprotein
Mucin 1 (MUC1; also known as episialin, PEM, H23Ag, EMA, CA15-3, and MCA) is a single pass type I transmembrane protein with a heavily glycosylated extracellular domain that extends up to 200–500 nm from the cell surface 1, 2. MUC1 (see Glossary) is normally expressed in the glandular or luminal epithelial cells of the mammary gland, esophagus, stomach, duodenum, pancreas, uterus, prostate, and lungs, and to a lesser extent, in hematopoietic cells 3, 4. It is absent in the skin epithelium and in
Structure of MUC1
The MUC1 gene encodes a single polypeptide chain which, due to conformational stress, is autoproteolytically cleaved immediately after translation at the GSVVV motif, located within the Sea urchin sperm protein enterokinase and agrin (SEA) domain, into two peptide fragments: the longer N-terminal subunit (MUC1-N) and the shorter C-terminal subunit (MUC1-C) (Figure 1A) 1, 10. Extracellularly, the two subunits remain associated through stable hydrogen bonds.
MUC1-N is composed of the proline,
Regulation of MUC1 gene expression
MUC1 is encoded by a gene located on the long arm (q) of chromosome 1 at position 21, a region frequently altered in breast cancer cells [25]. Overexpression of MUC1 in cancer is caused by increases in gene dosage and level of transcription, and by a loss of post-transcriptional regulation. Studies on epigenetic regulation have shown that methylation of histone H3-K9 and the CpG islands in the MUC1 promoter (close to the transcriptional start site; –174 to –182 bp) cause transcriptional
MUC1 isoforms
MUC1 contains seven exons, where exons 1–4 encode MUC1-N and exons 4–7 encode MUC1-C (Figure 2A). In humans, there are several isoforms of MUC1 that result from alternative splicing, exon skipping, and intron retention. A recent study identified 78 isoforms of MUC1 [30], with the most common isoforms being MUC1/A, MUC1/B, MUC1/C, MUC1/D, MUC1/X (or MUC1/Z), MUC1/Y, and MUC1/ZD. MUC1/A, MUC1/B, MUC1/C, and MUC1/D, encoding ‘full-length’ MUC1, arise from alternative splicing between sites located
Tumor-associated MUC1
TA-MUC1 differs from that expressed in normal cells, both in its biochemical features and its cellular distribution. Normally expressed MUC1 contains extensively branched Core 2 O-glycans (Figure 3A). By contrast, MUC1 in breast cancer cells mostly exhibits the Core 1 O-glycans [39] as loss of Core 2 β6-GlcNAc-transferase activity results in an absence of Core 2 O-glycans [40]. Additionally, TA-MUC1 is highly sialylated, which causes premature termination of chain elongation and formation of
Expression of TA-MUC1
MUC1 is overexpressed in cancer cells and the loss of cell polarity causes TA-MUC1 to be redistributed over the cell surface and within the cytoplasm (Figure 4) [3]. Lack of cell polarity also causes the redistribution of cell surface growth factors that are normally restricted to the basolateral surface of epithelial cells. Growth factors juxtaposed to MUC1 and intracellular kinases such as ZAP-70, PKC-γ, GSK-3β, and c-Src phosphorylate serine, tyrosine, and threonine residues on MUC1 CT (
The functional role of MUC1 in malignancy
The importance of MUC1 in disease progression is underscored by a study using mouse models of pancreatic and breast cancer. Muc1−/− mice expressing high levels of polyomavirus middle T antigen in the mammary gland spontaneously develop breast cancer but exhibit a substantial delay in disease progression and metastasis in comparison to Muc1+/+ mice [55]. Similarly, this trend was reported in a mouse model of spontaneous pancreatic ductal adenocarcinoma (PDA) 56, 57.
MUC1 as a cancer biomarker
Shed MUC1-N found in the circulation of cancer patients is used as a biomarker for cancer staging and monitoring relapse following therapy. For example, carbohydrate antigen 15.3 (CA 15.3, MUC1) and carbohydrate antigen 19.9 (CA 19.9, sLea antigen, found on several glycoproteins including MUC1) are commonly used for the detection of breast and pancreatic cancers, respectively 86, 87. Because MUC1-N is also released from stressed cells, the clinical utility of MUC1 measurement is confined to
Concluding remarks and future perspectives
Given the multifaceted functions of MUC1 in cancer, it is imperative to determine whether MUC1 plays an initiating role in carcinogenesis. We know that MUC1 is critical for the development of adenocarcinoma from preneoplastic PanIN lesions in the PDA mouse model 56, 57. In the absence of MUC1, PanIN lesions do not progress. Similarly, in the APCmin mouse of spontaneously developing colon polyps, MUC1 drives the polyps to become adenocarcinomas [101]. Thus, one can assume that MUC1 is crucial
Acknowledgments
We would like to acknowledge Dr Ian Marriott and Ms Tonya Bates for reviewing the manuscript for clarity.
References (116)
The epithelial mucin, MUC1, is expressed on resting T lymphocytes and can function as a negative regulator of T cell activation
Cell. Immunol.
(2000)The MUC1 SEA module is a self-cleaving domain
J. Biol. Chem.
(2005)Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin*
J. Biol. Chem.
(1990)High density O-glycosylation on tandem repeat peptide from secretory MUC1 of T47D breast cancer cells
J. Biol. Chem.
(1999)Molecular cloning and analysis of the mouse homologue of the tumor-associated mucin, MUC1, reveals conservation of potential O-glycosylation sites, transmembrane, and cytoplasmic domains and a loss of minisatellite-like polymorphism
J. Biol. Chem.
(1991)Tumor necrosis factor-α converting enzyme/ADAM 17 mediates MUC1 shedding
J. Biol. Chem.
(2003)Analysis of the promoter of the MUC1 gene overexpressed in breast cancer
FEBS Lett.
(1999)Novel MUC1 splice variants are expressed in cervical carcinoma
Gynecol. Oncol.
(2001)Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini
J. Biol. Chem.
(1990)A novel protein derived from the MUC1 gene by alternative splicing and frameshifting
J. Biol. Chem.
(2005)
Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response
Cancer Cell
MUC1 protein expression in tumor cells regulates transcription of proinflammatory cytokines by forming a complex with nuclear factor-κB p65 and binding to cytokine promoters: importance of extracellular domain
J. Biol. Chem.
The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts
J. Biol. Chem.
MUC1 mucin expression as a marker of progression and metastasis of human colorectal carcinoma
Gastroenterology
Sialyl Lewisx-mediated, PSGL-1-independent rolling adhesion on P-selectin
Biophys. J.
Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress
J. Biol. Chem.
Mucin 1 oncoprotein blocks hypoxia-inducible factor 1α activation in a survival response to hypoxia
J. Biol. Chem.
Inflammation and cancer: back to Virchow?
Lancet
MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli
Mucosal Immunol.
Muc1 cell surface mucin attenuates epithelial inflammation in response to a common mucosal pathogen
J. Biol. Chem.
ImMucin: a novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors
Vaccine
Structure and function of the cell surface (tethered) mucins
Annu. Rev. Physiol.
Epithelial mucin genes
Annu. Rev. Physiol.
MUC1, the renaissance molecule
J. Mammary Gland Biol. Neoplasia
MUC1: the polymorphic appearance of a human mucin
Glycobiology
Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis
J. Clin. Invest.
Inhibition of adhesion of S-fimbriated Escherichia coli to buccal epithelial cells by human milk fat globule membrane components: a novel aspect of the protective function of mucins in the nonimmunoglobulin fraction
Infect. Immun.
Mucins in cancer: function, prognosis and therapy
Nat. Rev. Cancer
Differential expression of MUC1, MUC2, and MUC5AC in carcinomas of various sites: an immunohistochemical study
Am. J. Clin. Pathol.
N-Glycosylation of the MUC1 mucin in epithelial cells and secretions
Glycobiology
Clathrin-mediated endocytosis of MUC1 is modulated by its glycosylation state
Mol. Biol. Cell
MT1-MMP mediates MUC1 shedding independent of TACE/ADAM17
Biochem. J.
The cytoplasmic tail of MUC1: a very busy place
Sci. Signal.
A minimal fragment of MUC1 mediates growth of cancer cells
PLoS ONE
MUC1* ligand, NM23-H1, is a novel growth factor that maintains human stem cells in a more naïve state
PLoS ONE
MUC1 is a substrate for γ-secretase
J. Cell. Biochem.
Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells
Int. J. Oncol.
The MUC1 extracellular domain subunit is found in nuclear speckles and associates with spliceosomes
PLoS ONE
Analysis of mammalian MUC1 genes reveals potential functionally important domains
Mamm. Genome
Frequent alteration of the DF3 tumor-associated antigen gene in primary human breast carcinomas
Cancer Res.
MUC1 expression is regulated by DNA methylation and histone H3 lysine 9 modification in cancer cells
Cancer Res.
Synergistic stimulation of MUC1 expression in normal breast epithelia and breast cancer cells by interferon-γ and tumor necrosis factor-α
J. Biol. Chem.
Mucin 1 oncoprotein expression is suppressed by the miR-125b oncomir
Genes Cancer
Human mucin MUC1 RNA undergoes different types of alternative splicing resulting in multiple isoforms
Cancer Immunol. Immunother.
Characterization and molecular cloning of a novel MUC1 protein, devoid of tandem repeats, expressed in human breast cancer tissue
Eur. J. Biochem.
Comparison of MUC-1 mucin expression in epithelial and non-epithelial cancer cell lines and demonstration of a new short variant form (MUC-1/Z)
Int. J. Cancer
MUC1 expression, splice variant and short form transcription (MUC1/Z, MUC1/Y) in prostate cell lines and tissue
BJU Int.
Preferential expression of novel MUC1 tumor antigen isoforms in human epithelial tumors and their tumor-potentiating function
Int. J. Cancer
The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein
Cancer Res.
A transfected sialyltransferase that is elevated in breast cancer and localizes to the medial/trans-Golgi apparatus inhibits the development of core-2-based O-glycans
J. Cell Biol.
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