title: Mathematical modelling unravels regulatory mechanisms of interferon-γ-induced STAT1 serine-phosphorylation and MUC4 expression in pancreatic cancer cells.
abstract: 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 IFN-γ induced serine-phosphorylation of STAT1 vary between cell types in contrast to conserved IFN-γ 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.
authors: Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany.
authors: C
authors: C
authors: Kossow
authors: D
authors: D
authors: Jose
authors: R
authors: R
authors: Jaster
authors: O
authors: O
authors: Wolkenhauer
authors: K
authors: K
authors: Rateitschak
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008954:Models, Biological; D055264:Mucin-4 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D055264:Mucin-4; D050794:STAT1 Transcription Factor; D012694:Serine; D007371:Interferon-gamma