GAGE, an antiapoptotic protein binds and modulates the expression of nucleophosmin/B23 and interferon regulatory factor 1

The GAGE family of highly related tumor antigens is expressed in a variety of tumors. This albeit silent gene expression resulted in resistance of cells to various apoptotic agents such as Fas, interferon-γ, Taxol, or γ-radiation. We now report that GAGE overexpression in either HeLa (expressing endogenous GAGE) or HEK293 (devoid of GAGE expression) rendered those cells unsusceptible to cell death induced by IFN-γ. We investigated the underlying mechanism of GAGE-induced cell survival upon treatment with IFN-γ in this report. We showed that GAGE overexpression resulted in down-regulation of a key player of IFN-γ-signaling pathway, interferon regulatory factor 1 (IRF1), and its target genes caspase-1 and caspase-7. An interaction between GAGE and IRF1 is detected in cells. Furthermore, GAGE interacted with a multifunctional protein nucleophosmin (NPM)/B23 and increased its abundance by stabilizing the protein. Increased level of NPM/B23 in conjunction with decreased level of IRF1 could aid GAGE-induced resistance to IFN-γ. Our results suggest that GAGE could rescue cell death induced by IFN-γ by altering the level of key players in cell death pathways. As GAGE is silent in most healthy tissues, targeting GAGE could result in therapeutic interventions in cancer therapy.