Functional Analysis Of IFITM1 Gene In Antiproliferative Action Of Interferon-gamma

Interferon-γ(IFN-γ) is a pleiotropic cytokine involved in antiproliferative and antivirus responses, immune surveillance and tumor suppression. These biological responses to IFN-γare mainly mediated by the regulation of gene expression. It has been reported that growth-inhibitory role of IFN-γis dependent on activation of signal transducers and activators of transcription 1 (STAT1), however, the molecular basis downstream of STAT1 remains unclear.In this study, we indicated that an IFN-γinduced gene, interferon induced transmembrane protein 1 (IFITM1), plays a key role in the antiproliferative action of IFN-γ. It has been reported that IFITM1 is induced by IFN-γin a STAT1 dependent manner. We demonstrated that overexpression of IFITM1 negatively regulated cell growth, whereas suppression of IFITM1 blocked the antiproliferative effect of IFN-γ, accelerated cell growth rate and conferred tumorigenicity to a nonmalignant hepatocyte in nude mice. Further, IFITM1 could enhance the transcriptional activity of p53 and stabilize the p53 protein by inhibiting p53 phosphorylation on Thr55. Suppression of p53 reduced the growth-inhibitory capacity of both IFITM1 and IFN-γ. These findings suggested that p53, downstream of IFITM1 signaling, might be involved in the growth inhibitory pathway of IFN-γ. Besides activating of p53 signaling, IFITM1 also can inhibit the activity of extracellular signal-regulated kinase (ERK). IFITM1 can interact with Caveolin-1, and enhance activity of Caveolin-1 to inhibit ERK activity. Therefore, these findings demonstrated that the antiproliferative action of IFN-γrequires the induction of IFITM, and provided a crosstalk between two well-known signaling mediators, STAT1 and p53, both of which play critical roles in tumor suppression.