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M104204200v1
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Papers In Press, published online ahead of print June 19, 2001
J. Biol. Chem, 10.1074/jbc.M104204200
Submitted on May 9, 2001
Revised on June 19, 2001
Accepted on June 19, 2001

Characterization of human mucin gene MUC4 promoter. Importance of growth factors and pro-inflammatory cytokines for its regulation in pancreatic cancer cells

Michaël Perrais, Pascal Pigny, Marie-Paule Ducourouble, Danièle Petitprez, Nicole Porchet, Jean-Pierre Aubert, and Isabelle Van Seuningen

Unité INSERM 377, Lille cedex 59045

Corresponding Author: vanseuni{at}lille.inserm.fr

Human mucin gene MUC4 encodes a large transmembrane mucin which is thought to play important roles in tumor cell biology, in ErbB2 signaling, and that is overexpressed in human pancreatic carcinomas. In this report, we describe the structure and functional activity of the 5’-flanking region, including 1.0 kb of the promoter. The long 5’-UTR (2.7 kb) is characterized by a high content of GC in its 3’-end. The first TATA box was located at -2672/-2668. Multiple transcription start sites and a high density of putative binding sites for Sp1 (GC and CACCC boxes), AP-1/-2/-4, CREB, GATA, GR and STAT transcription factors were found within the 5’-flanking region. Transcriptional activity of the promoter was assessed using pGL3-luciferase deletion mutants in two MUC4-expressing (CAPAN-1 and CAPAN-2) and one non-expressing (PANC-1) pancreatic cancer cell lines. Two highly active fragments (-219/-1 and –2781/-2572) that drive MUC4 transcription in CAPAN-1 and CAPAN-2 cells were identified. Gel-retardation assays indicated that Sp1 and Sp3 bind to cognate cis-elements found in the 5’-flanking region and that Sp1 transactivates whereas Sp3 inhibits the GC-rich region (-464/-1) in CAPAN-2 cells. Activation of PKC with phorbol ester and treatment of cells with EGF and TGF-alpha growth factors resulted in up-regulation of the promoter. TNF-alpha and IFN-gamma inflammatory cytokines had no or mild effect on MUC4 transcriptional activity when used alone. However, a very strong synergistic effect (10-12 fold activation) between IFN-gamma and TNF-alpha or IFN-gamma and TGF-alpha was obtained in CAPAN-2 cells. Altogether these results demonstrate that the 5’-flanking region of MUC4 contains epithelial cell-specific, positive and negative regulatory cis-elements, that Sp1/Sp3 are important regulators of MUC4 basal expression and that its regulation in pancreatic cancer cells is complex and involves PKC, MAPK, NF-kappa B and JAK/STAT signaling pathways


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