Disease relevance of Muc4

• Up-regulation of the Muc4/SMC gene in the 13762 sublines of the rat mammary adenocarcinoma correlates with the overexpression of transcription factor PEA3 and the receptor tyrosine kinase ErbB2 [1].
• Overexpression of Muc4/SMC has been shown to block cell-cell and cell-matrix interactions, protect tumor cells from immune surveillance, promote metastasis, and protect from apoptosis [2].
• Ascites sublines of the 13762 rat mammary adenocarcinoma have a cell surface sialomucin complex composed of the sialomucin ascites sialoglycoprotein-1 (ASGP-1) and the membrane-associated glycoprotein ASGP-2 [3].
• Using A375 human melanoma cells and MCF7 human breast adenocarcinoma cells stably transfected with tetracycline regulatable Muc4, we have investigated whether overexpression of Muc4/SMC can repress antibody binding to cell surface-expressed ErbB2 [4].

High impact information on Muc4

• All of these sublines contained a large mucin-type sialoglycoprotein (ASGP-1) as a major cell surface component [5].
• Mat-B1 and MAT-cMR6-S ASGP-1 molecules were sulfated, but MAT-C1 and MAT-MR2-S incorporated little sulfate [5].
• Concanavalin A (Con A)-induced anchorage of the major cell surface sialoglycoprotein component complex (ASGP-1/ASGP-2) was studied in 13762 rat mammary adenocarcinoma sublines with mobile (MAT-B1 subline) and immobile (MAT-C1 subline) cell surface Con A receptors [6].
• Treatment of cells, isolated microvilli, or microvillar membranes with Con A resulted in marked retention of ASGP-1 and ASGP-2, a Con A-binding protein, in cytoskeletal residues of both sublines obtained by extraction with Triton X-100 in PBS [6].
• Untreated membrane Triton residues retained very little ASGP-1/ASGP-2 complex [6].

Chemical compound and disease context of Muc4

• Ascites sublines of the highly metastatic 13762 rat mammary adenocarcinoma contain abundant amounts of a heterodimeric cell surface glycoprotein complex composed of a mucin subunit ASGP-1 (ascites sialoglycoprotein-1) and a transmembrane subunit (ASGP-2) [7].

Biological context of Muc4

• Muc4/SMC is tightly regulated in the rat mammary gland, low in the virgin, increased during pregnancy and lactation, and overexpressed in some aggressive mammary tumors [8].
• These data suggest that expression of PEA3 in mammary tumors leads to up-regulation of Muc4/SMC transcription, the gene product of which may contribute to the metastatic potential of mammary tumors [1].
• Here we report that PEA3 is capable of transactivating the Muc4/SMC promoter in a dose-dependent manner via direct attachment to a PEA3 binding site [1].
• Transcriptional activation of Muc4/SMC by PEA3 is potentiated by Ras and MEKK1 kinases [1].
• Since Muc4/SMC has been shown to be a potent anti-adhesive and a repressor of apoptosis, we propose that it plays a role in the non-apoptotic desquamation process [9].

Anatomical context of Muc4

• Investigations of primary rat mammary epithelial cells (MEC) have shown that Muc4/SMC expression is post-translationally regulated through inhibition of Muc4/SMC precursor processing by transforming growth factor-beta (TGF-beta) [8].
• Non-apoptotic desquamation of cells from corneal epithelium: putative role for Muc4/sialomucin complex in cell release and survival [9].
• Cloning and characterization of the 5' flanking region of the sialomucin complex/rat Muc4 gene: promoter activity in cultured cells [10].
• Muc4 was detected with 1G8 and other Muc4 antibodies in blood vessels from humans, rats and mice [11].
• In contrast, Neomarkers neu Ab1 antibody intensely stained the apical surface of the epithelium of the oviduct and the medial and basal layers of the stratified epithelia of the vagina, substantially overlapping the distribution of Muc4/SMC [12].

Associations of Muc4 with chemical compounds

• PEA3 transactivates the Muc4/sialomucin complex promoter in mammary epithelial and tumor cells [1].
• Muc4/sialomucin complex (SMC) is a heterodimeric glycoprotein complex derived from a single gene that is post-translationally processed into mucin (ASGP-1) and transmembrane (ASGP-2) subunits [8].
• Overall, the sequence predicts that ASGP-1 contains 2172 amino acids (M(r) 224,190), 43% of which are serine and threonine [7].
• Regulation of sialomucin complex/Muc4 expression in rat uterine luminal epithelial cells by transforming growth factor-beta: implications for blastocyst implantation [13].
• These results indicate that the TF antigen is present on the ASGP-2 transmembrane subunit of SMC/Muc4 from phenotypically normal tissues and cells, in contrast to malignant cells whose peanut lectin-binding disaccharide is located on ASGP-1 [14].

Physical interactions of Muc4

• ErbB2 and its ligand Muc4 (sialomucin complex) in rat lacrimal gland [15].

Regulatory relationships of Muc4

• SMAD2 antisense oligonucleotide blocks the inhibition of Muc4/SMC expression by TGF-beta [8].
• These results suggest that expression of SMC/Muc4 in mammary epithelial cells is regulated by selected growth factors through an ERK-dependent pathway at the transcript level [16].

Other interactions of Muc4

• Though mucins are not generally considered a product of the lacrimal gland, our results clearly show Muc4/SMC is produced by the gland in soluble and membrane forms [15].
• The TF antigen is also present on ASGP-2 of SMC/Muc4 produced by confluent cultures of Rama 37 rat mammary epithelial stem cells after their induction to an alveolar-like phenotype with prolactin [14].
• The half-time for appearance of glucosamine-labeled ASGP-1 at the cell surface was found to be greater than 4 h [17].
• The sialomucin complex (SMC), originally isolated as a heterodimeric glycoprotein complex from membranes of ascites sublines of a highly metastatic mammary adenocarcinoma, consists of a high Mr mucin subunit (ASGP-1, ascites sialoglycoprotein) and a transmembrane subunit (ASGP-2) with two epidermal growth factor-like domains [18].

Analytical, diagnostic and therapeutic context of Muc4

• Furthermore, Muc4/SMC and ErbB2 association in different tissues of the female reproductive tract was demonstrated by co-immunoprecipitation analysis [12].
• Thus none of these significant features of ASGP-1 that differed among the sublines correlated with xenotransplantation [5].
• Oligosaccharitols were released by alkaline borohydride treatments of ASGP-1 and purified by gel filtration, DEAE-Sephadex ion exchange chromatography, and high performance liquid chromatography [19].
• RESULTS: ASGP mRNA was detected by RT-PCR at 1 day after birth [20].
• In situ hybridization was performed to localize ASGP and rMuc5AC mRNA [20].

References