Mathematical modelling unravels regulatory mechanisms of interferon--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.

Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling

“…We and others have identified 5 STAT1 binding sites on MUC4 promoter, and two STAT3 binding sites on 5′-UTR of MUC4 [31, 32, 38], suggesting a possible role of STAT transcription factors in the transcriptional regulation of MUC4. Recently GS induced decrease in levels of phosphotyrosine STAT3 has been demonstrated in multiple myeloma and HNSCC cell lines [6, 9, 21].…”

“…Our laboratory and others have reported that activated STAT1 and STAT3 transcription factors are potential regulators of MUC4 expression in PC involving JAK pathway [31, 38–40]. Similarly, hyper activated STAT3 has been correlated with increased murine Muc4 levels in gastric tumors of mice [41].…”

Allergen‑removed Rhus�verniciflua Stokes suppresses invasion and migration of pancreatic cancer cells through downregulation of the JAK/STAT and Src/FAK signaling pathways

“…Several cytokines, including interleukin (IL)-4, IL-6, tumor necrosis factor-α and IFN-γ, have been reported to be involved in overexpression of MUC4 via the JAK/STAT pathway, particularly STAT1 and STAT3 (47). Previous studies regarding the MUC4 promoter have identified the binding sites for several transcription factors, including STAT1 and STAT3 (34,35,48). These findings suggested that the STAT transcription factors may have an important role in the transcriptional regulation of MUC4.…”

Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-β-treated human macrophages

“…Microarray studies have reported at least twenty genes induced by USTAT-1 in BJ fibroblast human line cells (Cheon and Stark 2009). Thirdly, another study proposed that USTAT-1 can act as a transcription factor (Kossow et al 2012). Additional studies will be necessary to fully understand the role of USTAT-1 in the nucleus of HIV infected MDM.…”