Abstract
MUC4 is a transmembrane mucin, which is aberrantly expressed in pancreatic adenocarcinoma with no detectable expression in the normal pancreas. Here, we present a novel mechanism of IFN-γ-induced expression of MUC4 in pancreatic cancer cells. Our studies highlight the upregulation of STAT-1 as a basis for MUC4 induction and demonstrate that its activation and upregulation by IFN-γ are two distinct, albeit temporally integrated, signalling events that drive the selective induction of IRF-1 and MUC4, respectively, within a single cell system. The profile of interferon regulatory factor (IRF)-1 gene induction by IFN-γ is consistent with its rapid transactivation by phospho-Y701-STAT-1. In contrast, the induction of the MUC4 mucin gene expression is relatively delayed, and occurs only in response to an increase in STAT-1 expression. A progressive binding of STAT-1 to various γ-interferon-activated sequences (GAS) in the MUC4 promoter is observed in chromatin immunoprecipitation assay, indicating its direct association. Stimulation of STAT-1 expression by double-stranded polynucleotides or ectopic expression is shown to induce MUC4 expression, without Y701 phosphorylation of STAT-1. This effect is abrogated by short interfering RNA (siRNA)-mediated inhibition of STAT-1 expression, supporting further the relevance of STAT-1 in MUC4 regulation. In conclusion, our findings identify a novel mechanism for MUC4 regulation in pancreatic cancer cells and unfold new perspectives on the foundation of IFN-γ-dependent gene regulation.
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Acknowledgements
This work was supported, in part, by an R01 grant CA78590 from the National Institutes of Health. We are grateful to Dr Robert Arceci (Johns Hopkins University) for providing the STAT-1 plasmid construct. We also thank Kristi LW Berger (Eppley Institute) for editorial assistance. This work was supported by an RO1 grant CA78590 from the National Institutes of Health.
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Andrianifahanana, M., Singh, A., Nemos, C. et al. IFN-γ-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-γ response. Oncogene 26, 7251–7261 (2007). https://doi.org/10.1038/sj.onc.1210532
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DOI: https://doi.org/10.1038/sj.onc.1210532
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