Interferon induced non‐STAT dependent pathway and tumor suppression

IFNs by inducing the transcription of IFN‐stimulated genes (ISG) regulate innate and acquired immune responses against tumors. IFN‐γ can also regulate genes in a non‐STAT dependent manner through transcription factor C/EBP‐β (CCAAT/Enhancer binding protein‐β). Using expression profiling, we recently identified several genes that are dependent on the IFN‐γ‐C/EBP‐β regulatory pathway for their expression. The Death‐Associated Protein Kinase 1(DAPK1), a tumor suppressor, is one such gene. The basal and IFN‐γ‐induced expression of dapk1 is critically dependent on C/EBP‐β. Further, C/EBP‐β dynamically associates with other transcription factors and co‐activators for inducing transcription of specific genes in a context‐ and signal‐ dependent manner. The Med1 subunit of the transcriptional mediator complex interacts with C/EBP‐β to induce dapk1 transcription. Interestingly, IFN‐γ induced MAPK signaling pathways regulate both C/EBP‐β and Med1. Both proteins are direct targets of ERK1/2 signaling. Consistent with these, the loss of Med1 expression corresponds to a loss of dapk1 expression in a number of human lung carcinomas. Together our studies reveal critical factors that regulate the anti‐metastatic effects of IFNs through a non‐STAT pathway.