title: Modulation of IFN-γ receptor 1 expression by AP-2α influences IFN-γ sensitivity of cancer cells.
abstract: Interferon (IFN)-γ plays crucial roles in regulating both innate and adaptive immunity. The existence of IFN-γ receptor 1 (IFNGR1) molecules on the cell surface is a prerequisite to the initiation of IFN-γ signaling; low expression of IFNGR1 leads to a functional blockade of IFN-γ signaling. However, the molecular mechanisms by which IFNGR1 expression is controlled are unclear. In the present study, we demonstrated that IFNGR1 expression was reduced or lost in breast cancer. Heterogeneous IFNGR1 immunoreactivity appeared to be associated with the morphological heterogeneity of breast cancer, and loss of IFNGR1 expression was predominantly observed in poorly differentiated areas. We identified the functional activating protein (AP)-2 and specificity protein (SP)-1 sites within the IFNGR1 promoter. Ectopic expression of AP-2α drastically repressed the expression of IFNGR1 and hindered IFN-γ signaling, whereas AP-2α gene silencing elevated IFNGR1 levels. Overexpression of SP-1 effectively antagonized the repressive effects of AP-2α. Simultaneous recruitment of both transcription factors to the AP-2 and SP-1 motifs, respectively, in the IFNGR1 promoter was demonstrated, implying that AP-2α and SP-1 may synergistically modulate IFNGR1 transcription. Moreover, AP-2α overexpression in AP-2-deficient SW480 cells remarkably inhibited Stat1 phosphorylation and the anti-proliferative effects of IFN-γ, whereas knockdown of the AP-2α expression dramatically enhanced the sensitivities of HeLa cells highly expressing AP-2 to IFN-γ, indicating that dysregulation of AP-2α expression is associated with impaired IFN-γ actions in cancer cells.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Changguo
authors.initials: C
authors.lastname: Chen
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Tianyou
authors.initials: T
authors.lastname: Wang
authors.forename: Lun
authors.initials: L
authors.lastname: Song
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.forename: Lu
authors.initials: L
authors.lastname: Qian
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000502:physiology; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D050656:Transcription Factor AP-2 / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D034741:RNA, Small Interfering; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D016329:Sp1 Transcription Factor; D050656:Transcription Factor AP-2; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human