MUC4

Mucin 4 (MUC 4) is a is_associated_with::mucin is_associated_with::protein that in humans is encoded by the MUC4 is_associated_with::gene. Like other mucins, MUC-4 is a high-molecular weight is_associated_with::glycoprotein.

The major constituents of is_associated_with::mucus, the viscous secretion that covers epithelial surfaces such as those in the trachea, colon, and cervix, are highly glycosylated proteins called mucins. These glycoproteins play important roles in the protection of the epithelial cells and have been implicated in epithelial renewal and differentiation. This gene encodes an integral membrane is_associated_with::glycoprotein found on the cell surface, although secreted isoforms may exist. At least two dozen transcript variants of this gene have been found, although for many of them the full-length transcript has not been determined or they are found only in tumor tissues.

MUC-4 has been found to play various roles in the progression of is_associated_with::cancer, particularly due to its signaling and anti-adhesive properties which contribute to tumor development and metastasis. It is also found to play roles in other diseases such as is_associated_with::endometriosis and is_associated_with::inflammatory bowel disease. MUC-4 belongs to the human mucin family that is membrane-anchored and can range in molecular weight from 550 to 930 kDa for the actual protein, and up to 4,650 kDa with is_associated_with::glycosylation.

Structure
MUC-4 is an O-glycoprotein that can reach up to 2 micrometers outside the cell. MUC-4 mucins consist of a large extracellular alpha subunit that is heavily glycosylated and a beta subunit that is anchored in the cell membrane and extends into the cytosol. This beta subunit is considered an is_associated_with::oncogene, whose role in cancer is increasingly being recognized particularly due to its involvement in signalling pathways, particularly with is_associated_with::ErbB2 (Her2). This subunit serves as a ligand for is_associated_with::ErbB2, which is suggested to cause the repression of apoptosis found in many cancer cells.

The large alpha subunit that is glycosylated likely confers the anti-adhesive properties to the cell, allowing for cell–cell and cell–matrix detachment in normal as well as cancerous cells. The heavy glycosylation may also serve as a reservoir for growth factors, which may become released upon degradation.

The two subunits of MUC-4 are transcribed from a single gene. Over 24 splice variants have been found for MUC4, in normal as well as abnormal tissue. Some forms are soluble, while others are membrane bound. Many polymorphisms are observed in the tandem repeat region of the alpha subunit, which has a variable number of repeats.

Normal
In normal functioning, MUC-4 is known to play anti-adhesive roles in the body, such as in lubricating the reproductive lining. It is also found in the is_associated_with::respiratory tract - particularly in the trachea and is_associated_with::lung - and the is_associated_with::digestive tract - in the is_associated_with::esophagus and colon - as well as in the visual and auditory systems. In these roles, MUC-4 serves to protect and lubricate the epithelium, which facilitates transport and traps foreign particles. One example of its function in the reproductive lining relates to blastocyst implantation resulting from MUC4 downregulation. It is found to be overexpressed during the luteal phase of is_associated_with::menstruation. MUC-4 may also have a role in fetal morphogenic development. It should be noted that MUC-4 is not found in the is_associated_with::gallbladder, is_associated_with::pancreas, or liver except in abnormal conditions such as cancer. MUC-4, however, may normally be found in bodily fluids like saliva, tears, and milk. In the soluble form, MUC-4 appears to lubricate the epithelial mucosa.

Disease
MUC-4 is thought to play a role in cancer progression by repressing is_associated_with::apoptosis and consequently increasing tumor cell proliferation. The molecular mechanism is thought to be through a MUC-4 complex with is_associated_with::ERBB2 receptors, which alters downstream signaling and down regulates is_associated_with::CDKN1B. The beta subunit of MUC-4 appears to serve as a ligand that causes the phosphorylation of is_associated_with::ErbB2, but does not activate the is_associated_with::MAPK or is_associated_with::AKT pathways. MUC-4 may also affect is_associated_with::HER2 signaling, and result in its stabilization. As a mucin, MUC-4 also alters adhesive properties of the cell. When overexpressed, the disorganization of mucins may reduce adhesion to other cells as well as the is_associated_with::extracellular matrix, promoting cancer cell migration and metastasis.

Pancreatic
MUC4 is often overexpressed in pancreatic adenocarcinomas and has been shown to promote tumor growth and metastasis, though the mechanism by which it does so is not known. MUC4 detection is emerging as a method to diagnose pancreatic cancer, especially since MUC4 is not detectably expressed in normal pancreas and increased expression of MUC-4 suggests a greater progression of the disease. Scientists have recently experimented with MUC4 inhibition in pancreatic cancer using drug delivery methods such as microRNAs. Such efforts have been successful at reducing is_associated_with::EGF receptor expression, its downstream signaling, and consequently malignant behavior of the cancer cell such as migration, invasion, and cell detachment.

Esophageal
MUC4 expression in esophageal cancer often leads to increased tumor proliferation and migration. Like with prostate cancer, increased expression of MUC4 suggests greater development of esophageal cancer. is_associated_with::Bile acids present in is_associated_with::gastroesophageal reflux disease are thought to contribute to this over-expression of MUC4. By inhibiting MUC-4, scientists have been able to reduce cancer cell proliferation, migration, and tumor size as well as reduce protein S100A4 expression, presenting MUC-4 as a good therapeutic target for the treatment of esophageal cancer.

Breast
Unlike pancreatic and esophageal cancers, MUC4 expression is suppressed in the is_associated_with::primary tumor when compared to normal cells. It, however, is found to be overexpressed in lymph node metastases. The initial reduction in MUC-4 appears to promote the transition to the primary tumor, but its subsequent increase in expression facilitate metastasis and ultimately increased malignancy

Other
MUC4 is found to be overexpressed in papillary thyroid carcinoma, and could serve as a potential marker of malignancy and prognosis. MUC-4 is also found to be a very sensitive and specific marker in low-grade fibromyxoid sarcoma,.

Role in other diseases
MUC-4 is also relevant to several other disease conditions. Polymorphisms in the MUC4 gene have been found to play a role in the progression of is_associated_with::endometriosis and related infertility, as well as dysplastic cervical disorders. MUC-4 also has important roles in is_associated_with::inflammatory bowel disease such as is_associated_with::Crohn's Disease and is found to be overexpressed in is_associated_with::ulcerative colitis.