Melan-A and Mucin Related Peptides、黑色素A和粘蛋白相關(guān)肽

Definition

Melan-A is a protein found on melanocytes. Antibodies to Melan-A is used for the diagnosis of melanoma. Mucins are heavily glycosylated proteins produced in epithelial tissues. There is a positive correlation between mucin secretion and cancer proliferation, invasiveness, metastasis.

Discovery

Coulie et al., in 1994 reported the identification of a gene that directs the expression of an antigen recognized on most melanomas by cytolytic T lymphocyte (CTL) clones that are restricted by HLA-A2. They designated gene as Melan-A1. Overexpression of the mucin proteins, MUC1 is known associated with many types of cancer 2. There are at least 19 human mucin genes have been distinguished by cDNA cloning 3.

Structural Characteristics

Melan-A, is 18 kb long and comprises five exons. Like the tyrosinase gene, it is expressed in most melanoma tumor samples and, among normal cells, only in melanocytes 1. The protein backbone of mucins has regions of high disulphide bonding, N-linked glycopeptides and tandem O-glycosylated repeats. The latter are multiple domains of homologous amino acid sequences having an N-acetylgalactosamine (GalNAc) monosaccharide added to near-neighbour serine (Ser) or threonine (Thr) amino acids. This monosaccharide, defined as the Tn antigen, can be further substituted with other monosaccharides, the most common being galactose (Gal) at C-3 to give the Thomsen-Friedenreich core (T antigen), and sialic acid (N-acetylneuraminic acid in humans) at C-3 of the Gal and/or C-6 of the GalNAc 

Mode of Action

Antitumor CTL clones can be isolated from blood lymphocytes of HLA-A2 melanoma patients, after stimulation in vitro with autologous tumor cells, and that some of these CTL clones lyse most HLA-A2 melanomas. The gene Melan-A directs the expression of an antigen recognized on most melanomas by CTL clones that are restricted by HLA-A21. Hyper secretion of airway mucin characterizes numerous respiratory diseases. Myristoylated alanine-rich C kinase substrate (MARCKS) is a central regulatory molecule linking secret agogue stimulation at the cell surface to mucin granule release by differentiated normal human bronchial epithelial cells in vitro. Down-regulation of MARCKS expression or disruption of MARCKS function in these cells inhibits the secretory response to subsequent stimulation. The intracellular mechanism controlling this secretory process involves cooperative action of two separate protein kinases, protein kinase C(PKC) and cGMP-dependent protein kinase. Upon stimulation, activated PKC phosphorylates MARCKS, causing translocation of MARCKS from the plasma membrane to the cytoplasm, where it is then dephosphorylated by a protein phosphatase 2A that is activated by cGMP-dependent protein kinase, and associates with both actin and myosin. Dephosphorylated cytoplasmic MARCKS would also be free to interact with mucin granule membranes and thus could link granules to the contractile cytoskeleton, mediating their movement to the cell periphery and subsequent exocytosis 4.

Functions

Marker for melanocytic tumors: Melan-A antigen is specific for the melanocyte lineage, found in normal skin, the retina, and melanocytes. It is a useful marker for melanocytic tumors (melanomas).

Barrier to particulate matter and microorganisms: Mucins are mucopolysaccharide or glycoprotein that is the chief constituent of mucus. These high molecular weight mucoproteins form a protective biofilm on the surface of epithelial cells, where they provide a barrier to particulate matter and microorganisms. Membrane-anchored mucins may have additional roles concerned with protein interactions at the cell surface.

Major secretory mucin expression in chronic sinusitis: The expression of 3 airway mucins, MUC2, MUC5AC, and MUC5B, was determined. An inverse relationship was identified between expression of MUC5AC and MUC2. Mucins may be used as markers for assessment of disease severity and may also help as prognostic indicators following medical or surgical treatment 5.

Roles of MUC4 in cancer: The MUC4 mucin is a transmembrane glycoprotein that is implicated in the pathogenesis of pancreatic cancer and is aberrantly expressed in many other epithelial carcinomas. Studies suggest its significant potential as a clinical tool for cancer diagnosis and prognosis. MUC4 modulates HER2/ErbB2 signaling and is a determinant of therapeutic outcome of Herceptin-based therapy, which further indicates its prospective usefulness in cancer therapy and treatment planning 6.

Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis: A direct association of the MUC4 mucin with the metastatic pancreatic cancer phenotype and provides experimental evidence for a functional role of MUC4 in altered growth and behavioral properties of the tumor cell 7.

References

Coulie PG, Brichard V, Van Pel A, Wolfel T, Schneider J, Traversari C, Mattei S, De Plaen E, Lurquin C, Szikora JP, Renauld JC, Boon T (1994). A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med.,180(1):35-42.

Niv Y (2008). MUC1 and colorectal cancer pathophysiology consideration. World J. Gastroenterol., 14(14):2139-2141.

Book: Mucin family of glycoproteins. Encyclopedia of Biological Chemistry by Perez-Vilar J, Hill, RL (2004).

Li Y, Martin LD, Spizz G, Adler KB (2001). MARCKS protein is a key molecule regulating mucin secretion by human airway epithelial cells in vitro. J Biol Chem., 276 (44): 40982-40990.

Ali MS, Hutton DA, Wilson JA, Pearson JP (2005). Major secretory mucin expression in chronic sinusitis. Otolaryngol Head Neck Surg., 133(3):423-428.

Singh AP, Chaturvedi P, Batra SK (2007). Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. Cancer Research, 67(2):433-436.

Singh AP, Moniaux N, Chauhan SC, Meza JL, Batra SK (2004). Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. Cancer Research, 64(2):622-630.