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J. Biol. Chem., Vol. 276, Issue 33, 30923-30933, August 17, 2001

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Characterization of Human Mucin Gene MUC4 Promoter
IMPORTANCE OF GROWTH FACTORS AND PROINFLAMMATORY 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^**

From the  Unité INSERM 377, Place de Verdun, 59045 Lille Cedex, France and the ^¶ Laboratoires d'Endocrinologie et  de Biochimie et de Biologie Moléculaire de l'Hôpital C. Huriez, CHRU, 59037 Lille Cedex, France

The human mucin gene MUC4 encodes a large transmembrane mucin that is thought to play important roles in tumor cell biology 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 kilobase of the promoter. The long 5'-untranslated region (2.7 kilobases) 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, cAMP-responsive element-binding protein, 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 nonexpressing (PANC-1) pancreatic cancer cell line. 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 protein kinase C with phorbol ester and treatment of cells with epidermal growth factor and transforming growth factor- resulted in up-regulation of the promoter. Tumor necrosis factor- and interferon (IFN)- 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- and tumor necrosis factor- or IFN- and transforming growth factor- 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 involves complex interplay between several signaling pathways.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF241535.

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