IFITM1 plays an essential role in the antiproliferative action of interferon-gamma.
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine involved in antiproliferative and anti-virus responses, immune surveillance and tumor suppression. These biological responses to IFN-gamma are mainly mediated by the regulation of gene expression. It has been reported that growth-inhibitory role of IFN-gamma is dependent on activation of signal transducers and activators of transcription 1 (STAT1); however, the molecular basis downstream of STAT1 remains unclear. Here, we report that an IFN-gamma-induced gene, interferon-induced transmembrane protein 1 (IFITM1), plays a key role in the antiproliferative action of IFN-gamma. Overexpression of IFITM1 negatively regulated cell growth, whereas suppression of IFITM1 blocked the antiproliferative effect of IFN-gamma, accelerated the cell growth rate and conferred tumorigenicity to a non-malignant hepatocyte in nude mice. Further, IFITM1 could inhibit the activity of extracellular signal-regulated kinase, 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-gamma. Therefore, these findings indicated that the antiproliferative action of IFN-gamma requires the induction of IFITM1, and provided a crosstalk between two well-known signaling mediators, STAT1 and p53, both of which play critical roles in tumor suppression.
Yang
G
G
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Xu
Y
Y
Chen
X
X
Hu
G
G
D000328:Adult; D000368:Aged; D000818:Animals; D000943:Antigens, Differentiation; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
D000943:Antigens, Differentiation; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; C062010:leu-13 antigen; D007371:Interferon-gamma; D010770:Phosphotransferases; D048049:Extracellular Signal-Regulated MAP Kinases