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MUC4: encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-ß, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-ß in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4+/Smad4-), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4-/Smad4+), were used. By RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-ß, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-ß induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-ß activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to histone deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-ß is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-ß as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.Oncogene (2004) 23, 5729-5738. doi:10.1038/sj.onc.1207769 Published online 7 June 2004 [ABSTRACT FROM AUTHOR]

The human MUC4 gene encodes a large membrane-associated mucin, characterized by a mucin tandem repeat domain and a growth factor-like transmembrane domain. In addition to the originally published sequence (sv0-MUC4 ), several MUC4 cDNA sequences (called sv1-MUC4 to sv21-MUC4 , MUC4/X , MUC4/Y ) from various tissues and cell lines have been recently described. They differ from sv0-MUC4 by deletions and/or insertions located in the 3′ region or, for two of them, by deletion of the central repetitive domain. To establish the nature of the mechanisms responsible for the diversity of MUC4 transcripts, the genomic structure of the 3′ region of the human MUC4 gene was determined. Our results show that it spans approximately 30.8 kb of genomic DNA and is composed of 24 exons, including one alternative exon which was exclusively reported for sv1-MUC4 . Moreover, we have shown that the different MUC4 transcripts are generated by several mechanisms, including the alternative use of cassette exons, exon skipping or use of cryptic splice donor/acceptor sites. [ABSTRACT FROM AUTHOR]

The MUC4 mucin gene encodes a putative membrane-anchored mucin with predicted size of 930 kDa, for its 26.5-kb allele. It is composed of two regions, the 850-kDa mucin-type subunit MUC4α and the 80-kDa membrane-associated subunit MUC4β. In this study, we cloned and characterized unique MUC4 cDNA sequences that differ from the originally published sequence. Eight alternative splice events located downstream of the central large tandem repeat array generated eight new, distinct cDNAs. The deduced sequences of these MUC4 cDNAs (sv1-MUC4 to sv8-MUC4, the full length cDNA being called sv0-MUC4) provided seven distinct variants, five secreted forms and two membrane-associated forms. Furthermore, two other alternative splicing events located on both sides of the tandem repeat array created two variants, MUC4/Y and MUC4/X, both lacking the central tandem repeat. Therefore, MUC4 can be expressed in three distinct forms, one membrane-bound, one secreted, and one lacking the hallmark feature of mucin, the tandem repeat array. Although no specific function has yet been discovered for the family of proteins putatively produced from the unique MUC4 gene, we suspect that the MUC4 proteins may be implicated in the integrity and renewal of the epithelium. [ABSTRACT FROM AUTHOR]