GAGE, an Antiapoptotic Protein Binds and Modulates the Expression of Nucleophosmin/B23 and Interferon Regulatory Factor 1

Abstract

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-gamma, Taxol, or gamma-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-gamma. We investigated the underlying mechanism of GAGE-induced cell survival upon treatment with IFN-gamma in this report. We showed that GAGE overexpression resulted in down-regulation of a key player of IFN-gamma-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-gamma. Our results suggest that GAGE could rescue cell death induced by IFN-gamma 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.

Rational drug design: A GAGE derived peptide kills tumor cells

“…GAGE also binds and increases the abundance of tumor suppressor NPM/B23. 9 Kondo et al has shown that NPM/B23 and IRF-1 exist as a complex and we have shown that GAGE could also be a part of the complex. 9,10 The above studies were performed with full length GAGE protein and we are interested in finding the region of GAGE that is responsible for its effect.…”

“…9 Kondo et al has shown that NPM/B23 and IRF-1 exist as a complex and we have shown that GAGE could also be a part of the complex. 9,10 The above studies were performed with full length GAGE protein and we are interested in finding the region of GAGE that is responsible for its effect. Small size of GAGE protein (117 amino acids) prompted us to design five peptides that could encompass whole sequence of GAGE protein.…”

“…We have shown that GAGE interacts with IFNg induced interferon regulatory factor-1 (IRF-1) and downregulates its expression. 9 IRF-1 is essential for IFNg induced apoptotic pathway. Decreased abundance of IRF-1 upon GAGE overexpression results in rescuing cells from IFNg induced cell death.…”

Plasticity and Virus Specificity of the Airway Epithelial Cell Immune Response during Respiratory Virus Infection

“…An unexpected family of tumor antigens, GAGE, was induced during RSV infection. These antiapoptotic tumor antigens are capable of interacting with IRF1 and of reducing its expression (27), which may help explain the weak interferon response observed in RSV-infected hAECs at both the transcriptional and protein levels. Our observations highlight the plasticity of the airway epithelium to elicit virus-specific immune effector responses.…”

Ectopic expression of embryonic stem cell and other developmental genes in cutaneous T-cell lymphoma

“…We and others have suggested that CT antigens during carcinogenesis may play an important role in maintaining cell survival (i.e., inhibition of apoptosis), [17][18][19] promoting resistance to various forms of chemo-and radio-therapy 20,21 and contributing to oncogenesis by targeting p53 and p21 tumor suppressor genes. 22,23 Also, since SYCP1 (Synaptonemal Complex Protein 1), SYCP3, DMC1 (Disrupted Meiotic cDNA 1), and REC8 CT antigens under normal conditions regulate generation of double strand DNA breaks during crossing over in meiosis, it was suggested that these genes may promote aneuploidy and genomic instability in cancers by producing aberrant chromosomal translocations.…”