Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany.
IET Syst Biol. 2012 Jun;6(3):73-85. doi: 10.1049/iet-syb.2011.0017.
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.
干扰素-γ (IFNγ) 通过上调信号转导子和转录激活子 (STAT) 1 介导信号转导，导致胰腺癌细胞中粘蛋白 (MUC) 4 基因的表达。STAT1 的上调也可能涉及 STAT1 酪氨酸或丝氨酸磷酸化。实验数据表明，与保守的 IFN-γ 诱导的 STAT1 酪氨酸磷酸化相反，IFN-γ 诱导的 STAT1 丝氨酸磷酸化在不同细胞类型中涉及的反应步骤不同。上述观察结果提出了以下两个问题：(i) IFNγ 刺激如何调节胰腺癌细胞系 CD18/HPAF 中 STAT1 的丝氨酸磷酸化？(ii) 哪种类型的 STAT1 作为 MUC4 的转录因子？我们的目标是通过数据驱动的数学建模来解决这两个问题。参数化常微分方程模型的模拟结果表明，未磷酸化的 STAT1 的丝氨酸磷酸化发生在细胞质中。相比之下，磷酸化的酪氨酸的 STAT1 的丝氨酸磷酸化可以发生在细胞质或细胞核中。此外，我们的结果表明，未磷酸化或丝氨酸磷酸化的 STAT1 可以单独通过逐步结合启动子中的不同位点，或者两者一起作为 MUC4 的转录因子。
