The human transmembrane mucin MUC4 is aberrantly expressed in 75% of pancreatic ductal adenocarcinomas, whereas no expression is found in normal pancreas. Therefore MUC4 appears as a useful biological marker for the diagnosis of ductal adenocarcinomas. Since rat Muc4 was shown to interact with ErbB-2 tyrosine kinase receptor and to either promote cell survival and differentiation or cell proliferation, it is postulated that MUC4 may also participate in pancreatic carcinogenesis. Our aim was to investigate in parallel the role of the Ets factor PEA3 in MUC4 and ErbB-2 transcriptional regulation in pancreatic cancer cells. Two MUC4-expressing WD (well-differentiated) (CAPAN-1 and -2) and one MUC4-non-expressing poorly differentiated (PANC-1) cell lines were used. The three cell lines express ErbB-2 at different levels. By co-transfection and site-directed mutagenesis, we show that PEA3 is a transactivator of the MUC4 promoter and that the −216 and −2368 PEA3 binding sites of the MUC4 promoter are essential. We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells. These results suggest that MUC4 is a new target gene of the Ets factor PEA3 in pancreatic cancer cells. In contrast, PEA3 represses the transcriptional activity of two fragments of the ErbB-2 promoter in a dose-dependent manner and decreases the endogenous ErbB-2 mRNA levels in WD cell lines. Thus, PEA3, by its capacity to up-regulate the epithelial marker MUC4 and to down-regulate the ErbB-2 oncogene, appears as a key regulator of the differentiation/proliferation balance in pancreatic cancer cells.
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Research Article|
February 08 2005
The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells
Valérie FAUQUETTE;
Valérie FAUQUETTE
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
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Michael PERRAIS;
Michael PERRAIS
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
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Sylvain CERULIS;
Sylvain CERULIS
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
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Nicolas JONCKHEERE;
Nicolas JONCKHEERE
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
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Marie-Paule DUCOUROUBLE;
Marie-Paule DUCOUROUBLE
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
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Jean-Pierre AUBERT;
Jean-Pierre AUBERT
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
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Pascal PIGNY;
Pascal PIGNY
1
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
†Université de Lille 2, Faculté de Médecine, 59045 Lille cedex, France
1To whom correspondence should be addressed (email pigny@lille.inserm.fr.).
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Isabelle Van SEUNINGEN
Isabelle Van SEUNINGEN
*Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
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Publisher: Portland Press Ltd
Received:
April 29 2004
Revision Received:
September 13 2004
Accepted:
October 05 2004
Accepted Manuscript online:
October 05 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 386 (1): 35–45.
Article history
Received:
April 29 2004
Revision Received:
September 13 2004
Accepted:
October 05 2004
Accepted Manuscript online:
October 05 2004
Citation
Valérie FAUQUETTE, Michael PERRAIS, Sylvain CERULIS, Nicolas JONCKHEERE, Marie-Paule DUCOUROUBLE, Jean-Pierre AUBERT, Pascal PIGNY, Isabelle Van SEUNINGEN; The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells. Biochem J 15 February 2005; 386 (1): 35–45. doi: https://doi.org/10.1042/BJ20040706
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