Regulation of interferon responses in medulloblastoma cells by interferon regulatory factor-1 and -2

Abstract

Summary Transcriptional activator interferon regulatory factor (IRF)-1 and repressor IRF-2 are known to play a critical role in the regulation of interferon (IFN) responses and oncogenesis in fibroblasts. Although these two factors are expressed in many tissues, including the brain, the role of IRFs in the central nervous system (CNS) has not been elucidated. We analysed a medulloblastoma cell line, ONS-76, as a CNSderived model system and generated its derivatives, Rl and R2 cells, which constitutively expressed each mouse IRF-1 and IRF-2 cDNA at high levels. By viral infection, Rl and R2 cells showed IFN-4 gene expression 3 h earlier than the control ONS-76 (C-76) cells, with 2.46-and 2.24-fold increase in IFN-,B production respectively. In the presence of cycloheximide, virally induced IFN-, gene expression of C-76 cells was suppressed, whereas Ri and R2 cells produced IFN-P 7.5-and 2.2-fold higher than C-76 cells respectively. On the other hand, induction of IFN-inducible genes was enhanced in Ri cells but was suppressed in R2 cells compared with C-76 cells. These results demonstrate that IRF-1 and IRF-2 may play an important role in the regulation of IFN-,B and IFN-inducible genes and that IRF-2 may have dual functions as an activator and repressor in CNS-derived cells.

Low expression of interferon regulatory factor‐1 and identification of novel exons skipping in patients with chronic myeloid leukaemia

“…These splicing aberrations in the IRF‐1 gene account for the loss of IRF‐1 expression and may constitute another general mechanism of tumour suppressor gene inactivation. Genetic alterations in the IRF‐1 gene have also been reported in other human cancers (Nozawa et al , 1998; Park et al , 1998; Tada et al , 1998). Changes in the relative balance between IRF‐1 and IRF‐2 lead to dysregulation of cell growth and may play a role in the development of neoplasias.…”