Mathematical modelling unravels regulatory mechanisms of interferon-γ-induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells

C. Kossow; D. Jose; R. Jaster; O. Wolkenhauer; K. Rateitschak

Mathematical modelling unravels regulatory mechanisms of interferon-γ-induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells

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Mathematical modelling unravels regulatory mechanisms of interferon-γ-induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells

Author(s): C. Kossow ; D. Jose ; R. Jaster ; O. Wolkenhauer ; K. Rateitschak
DOI: 10.1049/iet-syb.2011.0017

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Author(s): C. Kossow ¹ ; D. Jose ¹ ; R. Jaster ² ; O. Wolkenhauer ^{1, 3} ; K. Rateitschak ¹
- Affiliations: 1: Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
  2: Department of Medicine II, Division of Gastroenterology, Medical Faculty, University of Rostock, Rostock, Germany
  3: Department of Medicine II, Division of Gastroenterology, Medical Faculty, Stellenbosch Institute for Advanced Study (STIAS), Stellenbosch, South Africa
Source: Volume 6, Issue 3, June 2012, p. 73 – 85
DOI: 10.1049/iet-syb.2011.0017 , Print ISSN 1751-8849, Online ISSN 1751-8857

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Interferon-γ (IFNγ)-mediated signal transduction via upregulation of signal transducer and activator of transcription (STAT) 1 leads to the expression of the mucin (MUC) 4 gene in pancreatic cancer cells. Upregulation of STAT1 may also implicate STAT1 tyrosine- or serine-phosphorylation. Experimental data indicate that reaction steps involved in IFNγ-induced serine-phosphorylation of STAT1 vary between cell types in contrast to conserved IFNγ-induced tyrosine-phosphorylation of STAT1. The above observations raise the following two questions: (i) How does IFNγ stimulation regulates serine-phosphorylation of STAT1 in the pancreatic cancer cell line CD18/HPAF? (ii) Which type of STAT1 acts as a transcription factor of MUC4? Our objective is to address these two questions by data-driven mathematical modelling. Simulation results of the parameterised ordinary differential equation models show that serine-phosphorylation of unphosphorylated STAT1 occurs in the cytoplasm. In contrast, serine-phosphorylation of tyrosine-phosphorylated STAT1 can take place in the cytoplasm or in the nucleus. In addition, our results propose that unphosphorylated or serine-phosphorylated STAT1 can act as transcription factors of MUC4, either alone by progressive binding to different sites in the promoter or both together.

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Mathematical modelling unravels regulatory mechanisms of interferon-γ-induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells

Mathematical modelling unravels regulatory mechanisms of interferon-γ-induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells

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