IFN-gamma-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-gamma response
| Autor: | Nicolas Moniaux, Parmender P. Mehta, Moorthy P. Ponnusamy, Grish C. Varshney, Mahefatiana Andrianifahanana, C. Nemos, Surinder K. Batra, Ajay P. Singh |
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| Rok vydání: | 2007 |
| Předmět: |
Transcriptional Activation
Cancer Research medicine.medical_specialty Small interfering RNA Biology medicine.disease_cause Transactivation Interferon-gamma Downregulation and upregulation RNA interference Internal medicine Cell Line Tumor Gene expression Genetics medicine Humans Phosphorylation RNA Small Interfering Promoter Regions Genetic Molecular Biology Regulation of gene expression Base Sequence Mucin-4 Reverse Transcriptase Polymerase Chain Reaction Mucins Cell biology Up-Regulation Pancreatic Neoplasms Endocrinology STAT1 Transcription Factor Gene Expression Regulation Ectopic expression RNA Interference sense organs Carcinogenesis |
| Zdroj: | Oncogene. 26(51) |
| ISSN: | 0950-9232 |
| Popis: | 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-gamma-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-gamma 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-gamma 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 gamma-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-gamma-dependent gene regulation. |
| Databáze: | OpenAIRE |
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